Beta-ketoamide compounds with MCH antagonistic activity

ABSTRACT

Compounds of formula I  
                 
 
wherein the groups and residues A, B, b, X, Y, Z, R 1 , R 2 , R 3 , R 5a  and R 5b  have the meanings given in claim  1 . The invention further relates to pharmaceutical compositions containing at least one amide according to the invention. As a result of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia, and diabetes.

RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application60/554,229, filed Mar. 18, 2004, and priority to German patentapplication DE 10 2004 010 893.5, filed Mar. 6, 2004, each of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to new β-ketoamide compounds, thephysiologically acceptable salts thereof as well as their use as MCHantagonists and their use in preparing a pharmaceutical preparationwhich is suitable for the prevention and/or treatment of symptoms and/ordiseases caused by MCH or causally connected with MCH in some other way.The invention further relates to the use of a compound according to theinvention for influencing eating behavior and for reducing body weightand/or for preventing an increase in the body weight of a mammal. Theinvention also relates to compositions and medicaments containing acompound according to the invention, and processes for preparing them.Further objects of this invention relate to processes for preparing thecompounds according to the invention.

BACKGROUND OF THE INVENTION

The intake of food and its conversion in the body is an essential partof life for all living creatures. Therefore, deviations in the intakeand conversion of food generally lead to problems and also illness. Thechanges in the lifestyle and nutrition of humans, particularly inindustrialized countries, have promoted morbid excess weight (also knownas corpulence or obesity) in recent decades. In affected people, obesityleads directly to restricted mobility and a reduction in the quality oflife. There is the additional factor that obesity often leads to otherdiseases such as, for example, diabetes, dyslipidemia, high bloodpressure, arteriosclerosis, and coronary heart disease. Moreover, highbody weight alone puts an increased strain on the support and mobilityapparatus, which can lead to chronic pain and diseases such as arthritisor osteoarthritis. Thus, obesity is a serious health problem forsociety.

The term obesity means an excess of adipose tissue in the body. In thisconnection, obesity is fundamentally to be seen as the increased levelof fatness which leads to a health risk. There is no sharp distinctionbetween normal individuals and those suffering from obesity, but thehealth risk accompanying obesity is presumed to rise continuously as thelevel of fatness increases. For simplicity's sake, in the presentinvention, individuals with a Body Mass Index (BMI), which is defined asthe body weight measured in kilograms divided by the height (in meters)squared, above a value of 25 and more particularly above 30, arepreferably regarded as suffering from obesity.

Apart from physical activity and a change in nutrition, there iscurrently no convincing treatment option for effectively reducing bodyweight. However, as obesity is a major risk factor in the development ofserious and even life-threatening diseases, it is all the more importantto have access to pharmaceutical active substances for the preventionand/or treatment of obesity. One approach which has been proposed veryrecently is the therapeutic use of MCH antagonists (cf inter alia WO01/21577 and WO 01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consistingof 19 amino acids. It is synthesized predominantly in the hypothalamusin mammals and from there travels to other parts of the brain by theprojections of hypothalamic neurons. Its biological activity is mediatedin humans through two different G-protein-coupled receptors (GPCRs) fromthe family of rhodopsin-related GPCRs, namely the MCH receptors 1 and 2(MCH-1R and MCH-2R).

Investigations into the function of MCH in animal models have providedgood indications for a role of the peptide in regulating the energybalance, i.e., changing metabolic activity and food intake (D. Qu, etal., A role for melanin-concentrating hormone in the central regulationof feeding behaviour, Nature, 1996, 380 (6571), pp. 243-7; M. Shimada,et al., Mice lacking melanin-concentrating hormone are hypophagic andlean, Nature, 1998, 396 (6712), pp. 670-4). For example, afterintraventricular administration of MCH in rats, food intake wasincreased compared with control animals. Additionally, transgenic ratswhich produce more MCH than control animals, when given a high-fat diet,responded by gaining significantly more weight than animals without anexperimentally altered MCH level. It was also found that there is apositive correlation between phases of increased desire for food and thequantity of MCH mRNA in the hypothalamus of rats. However, experimentswith MCH knock-out mice are particularly important in showing thefunction of MCH. Loss of the neuropeptide results in lean animals with areduced fat mass, which take in significantly less food than controlanimals.

The anorectic effects of MCH are presumably mediated in rodents throughthe G_(αs)-coupled MCH-1R (B. Borowsky, et al., Antidepressant,anxiolytic and anorectic effects of a melanin-concentrating hormone-1receptor antagonist, Nat Med, 2002, 8 (8), pp. 825-30; Y. Chen, et al.,Targeted disruption of the melanin-concentrating hormone receptor-1results in hyperphagia and resistance to diet-induced obesity,Endocrinology, 2002, 143 (7), pp. 2469-77; D. J. Marsh, et al.,Melanin-concentrating hormone 1 receptor-deficient mice are lean,hyperactive, and hyperphagic and have altered metabolism, Proc Natl AcadSci USA, 2002. 99 (5), pp. 3240-5; S. Takekawa, et al., T-226296: anovel, orally active and selective melanin-concentrating hormonereceptor antagonist, Eur J Pharmacol, 2002, 438 (3), pp. 129-35), as,unlike primates, ferrets and dogs, no second MCH receptor subtype hashitherto been found in rodents. Loss of the MCH-1R in knock-out miceleads to a lower fat mass, an increased energy conversion and, when fedon a high fat diet, no increase in weight, compared with controlanimals. Another indication of the importance of the MCH system inregulating the energy balance results from experiments with a receptorantagonist (SNAP-7941) (B. Borowsky, et al., Nat Med, 2002, 8 (8), pp.825-30). In long term trials the animals treated with the antagonistlose significant amounts of weight.

In addition to its anorectic effect, the MCH-1R antagonist SNAP-7941also achieves additional anxiolytic and antidepressant effects inbehavioral experiments on rats (B. Borowsky, et al., Nat Med, 2002, 8(8), pp. 825-30). Thus, there are clear indications that the MCH-MCH-1Rsystem is involved not only in regulating the energy balance but also inaffectivity.

In the patent literature certain amine compounds are proposed as MCHantagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula

wherein Ar¹ denotes a cyclic group, X denotes a spacer, Y denotes a bondor a spacer, Ar denotes an aromatic ring which may be fused with anon-aromatic ring, R¹ and R² independently of one another denote H or ahydrocarbon group, while R¹ and R² together with the adjacent N atom mayform an N-containing hetero ring and R² with Ar may also form aspirocyclic ring, R together with the adjacent N atom and Y may form anN-containing hetero ring, as MCH antagonists for the treatment ofobesity, inter alia.

Moreover WO 01/82925 (Takeda) also describes compounds of formula

wherein Ar¹ denotes a cyclic group, X and Y represent spacer groups, Ardenotes an optionally substituted fused polycyclic aromatic ring, R¹ andR² independently of one another represent H or a hydrocarbon group,while R¹ and R² together with the adjacent N atom may form anN-containing heterocyclic ring and R² together with the adjacent N atomand Y may form an N-containing hetero ring, as MCH antagonists for thetreatment of obesity.

The aim of the present invention is to provide new β-ketoamidecompounds, particularly those which are effective as MCH antagonists.

The invention also sets out to provide new β-ketoamide compounds whichcan be used to influence the eating habits of mammals and achieve areduction in body weight, particularly in mammals, and/or prevent anincrease in body weight.

The present invention further sets out to provide new pharmaceuticalcompositions which are suitable for the prevention and/or treatment ofsymptoms and/or diseases caused by MCH or otherwise causally connectedto MCH. In particular, the aim of this invention is to providepharmaceutical compositions for the treatment of metabolic disorderssuch as obesity and/or diabetes as well as diseases and/or disorderswhich are associated with obesity and diabetes. Other objectives of thepresent invention are concerned with demonstrating advantageous uses ofthe compounds according to the invention. The invention also sets out toprovide a process for preparing the amide compounds according to theinvention. Other aims of the present invention will be immediatelyapparent to the skilled man from the foregoing remarks and those thatfollow.

SUMMARY OF THE INVENTION

The invention relates firstly to β-ketoamide compounds of generalformula I

wherein:

-   R¹ and R² independently of one another denote H, a C₁₋₈-alkyl, or    C₃₋₇-cycloalkyl group optionally mono- or polysubstituted by the    group R¹¹, while a —CH₂— group in position 3 or 4 of a 5-, 6-, or    7-membered cycloalkyl group may be replaced by —O—, —S—, or —NR¹³—,    or a phenyl or pyridinyl group optionally mono- or polysubstituted    by the group R²⁰ and/or monosubstituted by nitro, or-   R¹ and R² form a C₂₋₈-alkylene bridge, wherein one or two —CH₂—    groups independently of one another may be replaced by —CH═N— or    —CH═CH— and/or one or two —CH₂-groups independently of one another    may be replaced by —O—, —S—, —SO—, —(SO₂)—, —C(═CH₂)—, or —NR¹³— in    such a way that heteroatoms are not directly joined together, and    that a group —CO— is not directly linked to the group R¹R²N—, while    in the alkylene bridge defined hereinbefore one or more H atoms may    be replaced by R¹⁴, and the alkylene bridge defined hereinbefore may    be substituted by one or two identical or different carbo- or    heterocyclic groups Cy such that the bond between the alkylene    bridge and the group Cy is made via a single or double bond, via a    common C atom forming a spirocyclic ring system, via two common    adjacent C and/or N atoms forming a fused bicyclic ring system or    via three or more C and/or N atoms forming a bridged ring system;-   R³ denotes H, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₄-alkyl, or phenyl-C₁₋₃-alkyl;-   X denotes a C₁₋₈-alkylene bridge, wherein a —CH₂— group which is not    directly linked to the group R¹R²N— may be replaced by —CH═CH— or    —C═C— and/or one or two non-adjacent —CH₂— groups, which are not    directly linked to the group R¹R²N—, may be replaced independently    of one another by —O—, —S—, —(SO)—, —(SO₂)—, —CO—, or —NR⁴— in such    a way that in each case two O, S, or N atoms or an O and an S atom    are not directly joined together, while the bridge X may be    connected to R¹ including the N atom linked to R¹ and X, forming a    heterocyclic group, while the bridge X may additionally also be    connected to R² including the N atom connected to R² and X, forming    a heterocyclic group, and while two C atoms or a C and an N atom of    the alkylene bridge may be joined together by an additional    C₁₋₄-alkylene bridge, and a C atom not directly connected to a    heteroatom may be substituted by R¹⁰ and/or one or two C atoms may    be substituted in each case by one or two identical or different    substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl, and    C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenyl    substituents may be joined together, forming a carbocyclic ring    system;-   Z denotes a single bond or —CR^(7a)R^(7b)—CR^(7c)R^(7d)—;-   Y has one of the meanings given for Cy, while R¹ may be connected to    Y including the group X and the N atom connected to R¹ and X,    forming a heterocyclic group fused to Y, and/or X may be connected    to Y forming a carbo- or heterocyclic group fused to Y;-   A has one of the meanings given for Cy;-   B has one of the meanings given for Cy;-   b has the value 0 or 1;-   Cy denotes a carbo- or heterocyclic group selected from one of the    following meanings:    -   a saturated 3- to 7-membered carbocyclic group, an unsaturated        4- to 7-membered carbocyclic group, a phenyl group, a saturated        4- to 7-membered or unsaturated 5- to 7-membered heterocyclic        group with an N, O, or S atom as heteroatom, a saturated or        unsaturated 5- to 7-membered heterocyclic group with two or more        N atoms or with one or two N atoms and one O or S atom as        heteroatoms, an aromatic heterocyclic 5- or 6-membered group        with one or more identical or different heteroatoms selected        from N, O, and/or S, while the abovementioned 4-, 5-, 6-, or        7-membered groups may be fused to a phenyl or pyridine ring via        two common adjacent C atoms, and in the abovementioned 5-, 6-,        or 7-membered groups one or two non-adjacent —CH₂ groups may be        replaced independently of one another by a —CO—, —C(═CH₂)—,        —(SO)—, or —(SO₂)— group, and    -   the abovementioned saturated 6- or 7-membered groups may also be        present as bridged ring systems with an imino,        N—(C₁₋₄-alkyl)-imino, methylene, C₁₋₄-alkyl-methylene, or        di-(C₁₋₄-alkyl)-methylene bridge, and    -   the abovementioned cyclic groups may be mono- or polysubstituted        by R²⁰ at one or more C atoms, in the case of a phenyl group may        also additionally be monosubstituted by nitro, and/or one or        more NH groups may be substituted by R²¹;-   R⁴ has one of the meanings given for R¹⁷ or denotes C₃₋₆-alkenyl or    C₃₋₆-alkynyl,-   R^(5a) and R^(5b) independently of one another denote H, C₁₋₃-alkyl,    C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, CF₃, F, or Cl, while    R^(5a) and R^(5b) representing alkyl may be joined together such    that a C₃₋₇-cycloalkyl group is formed together with the C atom to    which R^(5a) and R^(5b) are linked,-   R^(7a) and R^(7c) independently of one another denote H, F, Cl,    C₁₋₄-alkyl, or CF₃,-   R^(7b) and R^(7d) independently of one another denote H, F,    C₁₋₄-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, or CF₃,-   while R^(7a) and R^(7b) representing alkyl may be joined together    such that a C₃₋₇-cycloalkyl group is formed together with the C atom    to which R^(7a) and R^(7b) are linked, and/or R^(7c) and R^(7d)    representing alkyl may be joined together such that a    C₃₋₇-cycloalkyl group is formed together with the C atom to which    R^(7c) and R^(7d) are linked, or R^(7b) and R^(7d) representing    alkyl may be joined together such that a C₃₋₇-cycloalkyl group is    formed together with the two C atoms to which R^(7b) and R^(7d) are    linked;-   R¹⁰ denotes hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy,    (C₁₋₄-alkoxy)-C₁₋₃-alkyl, carboxy, C₁₋₄-alkoxycarbonyl, amino,    C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino,    amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,    di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,    cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl, amino-C₁₋₃-alkoxy,    C₁₋₄-alkyl-amino-C₁₋₃-alkoxy, di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkoxy,    cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkoxy, aminocarbonyl,    C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl, or    cyclo-C₃₋₆-alkyleneimino-carbonyl;-   R¹¹ denotes C₁₋₃-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, R¹⁵—O—,    R¹⁵—O—C₁₋₃-alkyl-, R¹⁵—O—CO—, R¹⁵—CO—O—, cyano, R¹⁶R¹⁷N—,    R¹⁸R¹⁹N—CO—, or Cy;-   R¹³ has one of the meanings given for R¹⁷;-   R¹⁴ denotes halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, R¹⁵—O—,    R¹⁵—O—CO—, R¹⁵—CO, R¹⁵—CO—O—, R¹⁶R¹⁷N—, R¹⁸R¹⁹N—CO—,    R¹⁵—O—C₁₋₃-alkyl, R¹⁵—O—CO—C₁₋₃-alkyl, R¹⁵—O—CO—NH—, R¹⁵—SO₂—NH,    R¹⁵—O—CO—NH—C₁₋₃-alkyl, R¹⁵—SO₂—NH—C₁₋₃-alkyl, R¹⁵—CO—C₁₋₃-alkyl,    R¹⁵—CO—O—C₁₋₃-alkyl, R¹⁶R⁷N—C₁₋₃-alkyl, R¹⁸R¹⁹N—CO—C₁₋₃-alkyl, or    Cy—C₁₋₃-alkyl-;-   R¹⁵ denotes H, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, phenyl, phenyl-C₁₋₃-alkyl, pyridinyl, or    pyridinyl-C₁₋₃-alkyl;-   R¹⁶ denotes H, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl,    C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, hydroxy-C₂₋₃-alkyl,    C₁₋₄-alkoxy-C₂₋₃-alkyl, amino-C₂₋₆-alkyl,    C₁₋₄-alkyl-amino-C₂₋₆-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl, or    cyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl;-   R¹⁷ has one of the meanings given for R¹⁶ or denotes phenyl,    phenyl-C₁₋₃-alkyl, pyridinyl, dioxolan-2-yl, C₁₋₄-alkylcarbonyl,    hydroxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxycarbonyl,    C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonylamino-C₂₋₃-alkyl,    N—(C₁₋₄-alkylcarbonyl)-N—(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl,    C₁₋₄-alkylsulfonyl, C₁₋₄-alkylsulfonylamino-C₂₋₃-alkyl, or    N—(C₁₋₄-alkylsulfonyl)-N—(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl-,-   R¹⁸ and R¹⁹ independently of one another denote H or C₁₋₆-alkyl;-   R²⁰ denotes halogen, hydroxy, cyano, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,    hydroxy-C₁₋₄-alkyl, R²²—C₁₋₃-alkyl, or has one of the meanings given    for R²²;-   R²¹ denotes C₁₋₄-alkyl, hydroxy-C₂₋₃-alkyl, C₁₋₄-alkoxy-C₂₋₆-alkyl,    C₁₋₄-alkyl-amino-C₂₋₆-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl,    cyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl, phenyl-C₁₋₃-alkyl,    C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxy-carbonyl, or C₁₋₄-alkylsulfonyl;    and-   R²² denotes phenyl-C₁₋₃-alkoxy,    cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkoxy, C₁₋₄-alkoxy, C₁₋₄-alkylthio,    carboxy, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, aminocarbonyl,    C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,    cyclo-C₃₋₆-alkyl-amino-carbonyl, cyclo-C₃₋₆-alkyleneimino-carbonyl,    cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl-aminocarbonyl,    phenylaminocarbonyl, C₁₋₄-alkyl-sulfonyl, C₁₋₄-alkyl-sulfinyl,    C₁₋₄-alkyl-sulfonylamino, amino, C₁₋₄-alkylamino,    di-(C₁₋₄-alkyl)-amino, C₁₋₄-alkyl-carbonyl-amino,    cyclo-C₃₋₆-alkyleneimino, phenyl-C₁₋₃-alkylamino,    N—(C₁₋₄-alkyl)-phenyl-C₁₋₃-alkylamino, acetylamino, propionylamino,    phenylcarbonylamino, phenylcarbonylmethylamino,    hydroxy-C₁₋₃-alkylaminocarbonyl, (4-morpholinyl)carbonyl,    (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl,    (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl,    aminocarbonyl-amino, or C₁₋₄-alkylaminocarbonyl-amino,-   while in the abovementioned groups and radicals, particularly in X,    R¹ to R⁴, R¹⁰, R¹¹, and R¹³ to R²², in each case one or more C atoms    may additionally be mono- or polysubstituted by F and/or in each    case one or two C atoms independently of one another may    additionally be monosubstituted by Cl or Br and/or in each case one    or more phenyl rings may independently of one another additionally    comprise one, two, or three substituents selected from the group F,    Cl, Br, I, C₁₋₄-alkyl, C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl,    hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino,    aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy,    amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl, and    di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl and/or may be monosubstituted by    nitro, and-   the H atom of a carboxy group present or an H atom bound to an N    atom in each case may be replaced by a group which can be cleaved in    vivo,-   the tautomers, the diastereomers, the enantiomers, the mixtures    thereof, and the salts thereof.

The compounds according to the present invention, including thephysiologically acceptable salts, are especially effective asantagonists of the MCH receptor, particularly the MCH-1 receptor, andexhibit very good affinity in MCH receptor binding studies. In addition,the compounds according to the invention have a high to very highselectivity with regard to the MCH receptor. Generally the compoundsaccording to the invention have low toxicity, they are well absorbed byoral route and have good intracerebral transitivity, particularly brainaccessibility.

The invention also relates to the compounds in the form of theindividual optical isomers, mixtures of the individual diastereomers,enantiomers, or racemates, in the form of the tautomers and in the formof the free bases or the corresponding acid addition salts withpharmacologically safe acids. The subject of the invention also includesthe compounds according to the invention, including their salts, whereinone or more hydrogen atoms are replaced by deuterium.

This invention also includes the physiologically acceptable salts of theβ-ketoamide compounds according to the invention as described above andhereinafter.

Also covered by this invention are compositions containing at least oneβ-ketoamide compound according to the invention and/or a salt accordingto the invention optionally together with one or more physiologicallyacceptable excipients.

Also covered by this invention are pharmaceutical compositionscontaining at least one β-ketoamide compound according to the inventionand/or a salt according to the invention optionally together with one ormore inert carriers and/or diluents.

The invention also relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for influencing the eating behavior of a mammal.

The invention also relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for reducing the body weight and/or for preventing an increasein the body weight of a mammal.

The invention also relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition with anMCH-receptor-antagonistic activity, particularly with anMCH-1-receptor-antagonistic activity.

Moreover, the invention relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of symptoms and/or diseases whichare caused by MCH or are otherwise causally connected with MCH.

The invention also relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of metabolic disorders and/or eatingdisorders, particularly obesity, bulimia, bulimia nervosa, cachexia,anorexia, anorexia nervosa, and hyperphagia.

This invention also relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of diseases and/or disordersassociated with obesity, particularly diabetes, especially type IIdiabetes, complications of diabetes including diabetic retinopathy,diabetic neuropathy, diabetic nephropathy, insulin resistance,pathological glucose tolerance, encephalorrhagia, cardiac insufficiency,cardiovascular diseases, particularly arteriosclerosis and high bloodpressure, arthritis, and gonitis.

Moreover, the invention relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of hyperlipidemia, cellulitis, fataccumulation, malignant mastocytosis, systemic mastocytosis, emotionaldisorders, affective disorders, depression, anxiety, sleep disorders,reproductive disorders, sexual disorders, memory disorders, epilepsy,forms of dementia, and hormonal disorders.

Another object of the invention is the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of micturition disorders, such as,for example, urinary incontinence, hyperactive urinary bladder, urgency,nycturia, and enuresis.

The invention further relates to the use of at least one β-ketoamidecompound according to the invention and/or a salt according to theinvention for preparing a pharmaceutical composition which is suitablefor the prevention and/or treatment of dependencies and/or withdrawalsymptoms.

Furthermore the invention relates to processes for preparing apharmaceutical composition according to the invention, characterized inthat at least one β-ketoamide compound according to the invention and/ora salt according to the invention is incorporated in one or more inertcarriers and/or diluents by a non-chemical method.

The invention further relates to a pharmaceutical composition containinga first active substance selected from the β-ketoamide compoundsaccording to the invention and/or the corresponding salts and a secondactive substance selected from the group consisting of active substancesfor the treatment of diabetes, active substances for the treatment ofdiabetic complications, active substances for the treatment of obesity,preferably other than MCH antagonists, active substances for thetreatment of high blood pressure, active substances for the treatment ofdyslipidemia or hyperlipidemia, including arteriosclerosis, activesubstances for the treatment of arthritis, active substances for thetreatment of anxiety states, and active substances for the treatment ofdepression, optionally together with one or more inert carriers and/ordiluents.

The invention also relates to a process for preparing β-ketoamidecompounds of formula I

wherein A, B, b, X, Y, Z, R¹, R², R³, R^(5a), and R^(5b) have themeanings given hereinbefore and hereinafter, wherein an amine compoundof formula A1

where X, Y, Z, R¹, R², and R³ have the meanings given hereinbefore andhereinafter, is reacted with a carboxylic acid compound or a carboxylicacid derivative of formula A2

where A, B, b, R^(5a), and R^(5b) are as hereinbefore defined, and thegroup M denotes OH, Cl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, or C₁₋₆-alkyl-COO—,in the presence of at least one base, in a solvent or mixture ofsolvents.

This invention further relates to a process for preparing β-ketoamidecompounds of formula I

where A, B, b, X, Y, Z, R¹, R², and R³ have the meanings givenhereinbefore and hereinafter, wherein a propynoic acid amide compound offormula B1

where A, B, b, X, Y, Z, R¹, R², and R³ are as hereinbefore defined, ishydrolyzed by the addition of an acid or base in a solvent or mixture ofsolvents and optionally in the presence of an activating nucleophile.

The starting materials and intermediate products used in the synthesisaccording to the invention, particularly the compounds of formula A1,A2, and B1, are also a subject of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, the groups, residues and substituents,particularly A, B, X, Y, Z, R¹ to R⁴, R^(5a), R^(5b), R^(7a), R^(7b),R^(7c), R^(7d), R¹⁰, R¹¹, R¹³ to R²², and the index b have the meaningsgiven hereinbefore.

If groups, residues and/or substituents occur more than once in acompound, they may have the same or different meanings in each case.

According to the invention the tautomers of the compounds of formula I,particularly the enol tautomers of the keto form represented by formulaI, are also included.

In the event that R^(5b) denotes a H atom, the following compounds areincluded according to the invention, while formula I (keto) indicatesthe keto form and formula I (enol) indicates the associated enol form:

In the embodiments and Examples described hereinafter, only the ketoform is explicitly mentioned; the corresponding enol form which isreadily obtainable by anyone skilled in the art is also included inevery case, according to the invention.

Particularly preferred definitions of the groups R^(5a), R^(5b) are ineach case independently of one another H, F, Cl, CF₃, methyl, and ethyl,particularly H, F, methyl, and ethyl, particularly preferably H, F, andmethyl. According to another preferred embodiment R^(5a) and R^(5b)representing methyl are joined together in such a way that a cyclopropylgroup is formed together with the C atom to which R^(5a) and R^(5b) arelinked.

Most particularly preferably R^(5a) and R^(5b) denote H.

Preferred meanings of the substituent R³ are H, C₁₋₄-alkyl,C₃₋₆-cycloalkyl, or C₃₋₆-cycloalkyl-C₁₋₃-alkyl; particularly H orC₁₋₃-alkyl. Particularly preferably R³ denotes H or methyl, particularlyH.

The substituents R¹ and R² may have the meanings given above andhereinafter as separate groups or may be connected to one another as abridge. For simplicity's sake, the preferred meanings of R¹ and R² asseparate groups will be described first of all and then the preferredmeanings of the groups R¹ and R² connected to one another to form abridge will be given. Preferred compounds according to the inventiontherefore have one of the preferred meanings of R¹ and R², describedbelow, as separate groups, combined with one of the preferred meaningsof R¹ and R², described hereinafter, as groups connected to one anotherto form a bridge.

If R¹ and R² are not joined together via an alkylene bridge, R¹ and R²independently of one another preferably denote a C₁₋₈-alkyl orC₃₋₇-cycloalkyl group optionally mono- or polysubstituted by the groupR¹¹, while a —CH₂— group in position 3 or 4 of a 5-, 6-, or 7-memberedcycloalkyl group may be replaced by —O—, —S—, or —NR¹³—, or a phenyl orpyridinyl group optionally mono- or polysubstituted by the group R²⁰and/or monosubstituted by nitro, while one of the groups R¹ and R² mayalso represent H.

In the groups R¹ and R² one or more C atoms may be mono- orpolysubstituted by F and/or one or two C atoms independently of oneanother may be monosubstituted by Cl, Br, or CN.

Preferred meanings of the group R¹¹ are C₁₋₃-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, R¹⁵—O—, cyano, R¹⁶R¹⁷N—, C₃₋₇-cycloalkyl,cyclo-C₃₋₆-alkyleneimino, pyrrolidinyl, —N—(C₁₋₄-alkyl)-pyrrolidinyl,piperidinyl, N—(C₁₋₄-alkyl)-piperidinyl, phenyl, and pyridyl, while inthe abovementioned groups and residues one or more C atoms may be mono-or polysubstituted by F and/or one or two C atoms independently of oneanother may be monosubstituted by Cl, Br, or CN, and the abovementionedcyclic groups may be mono- or polysubstituted by R²⁰ at one or more Catoms, in the case of a phenyl group may also additionally bemonosubstituted by nitro, and/or one or more NH groups may besubstituted by R²¹. If R¹¹ has one of the meanings R¹⁵—O—, cyano,R¹⁶R¹⁷N— or cyclo-C₃₋₆-alkyleneimino, the C atom of the alkyl orcycloalkyl group substituted by R¹¹ is preferably not directly connectedto a heteroatom, such as, for example, the group —N—X.

Preferably the groups R¹ and R² independently of one another denote H,C₁₋₆-alkyl, C₃₋₅-alkenyl, C₃₋₅-alkynyl, C₃₋₇-cycloalkyl,hydroxy-C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,(hydroxy-C₃₋₇-cycloalkyl)-C₁₋₃-alkyl, hydroxy-C₂₋₄-alkyl, NC—C₂₋₃-alkyl,C₁₋₄-alkoxy-C₂₋₄-alkyl, hydroxy-C₁₋₄-alkoxy-C₂₋₄-alkyl,C₁₋₄-alkoxy-carbonyl-C₁₋₄-alkyl, carboxyl-C₁₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₄-alkyl-amino-C₂₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl, pyrrolidin-3-yl,N—(C₁₋₄-alkyl)-pyrrolidinyl, pyrrolidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-pyrrolidinyl-C₁₋₃-alkyl, piperidin-3-yl, or -4-yl,N—(C₁₋₄-alkyl)-piperidin-3-yl, or -4-yl, piperidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-piperidinyl-C₁₋₃-alkyl, tetrahydropyran-3-yl,tetrahydropyran-4-yl, tetrahydropyranyl-C₁₋₃-alkyl,tetrahydrofuran-3-yl, tetrahydrofuranyl-C₁₋₃-alkyl, phenyl,phenyl-C₁₋₃-alkyl, pyridyl, or pyridyl-C₁₋₃-alkyl, while in theabovementioned groups and residues one or more C atoms may be mono- orpolysubstituted by F and/or one or two C atoms, particularly one C atom,may be monosubstituted independently of one another with Cl or Br, andthe phenyl or pyridyl group may be mono- or polysubstituted by the groupR²⁰ and/or monosubstituted by nitro. Preferably the abovementionedcycloalkyl rings may be mono- or polysubstituted by substituentsselected from hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyl, or C₁₋₃-alkyloxy,particularly hydroxy, hydroxymethyl, methyl, and methoxy. Preferablyalso, the C₂₋₄-alkyl bridges in the definitions hydroxy-C₂₋₄-alkyl andC₁₋₄-alkoxy-C₂₋₄-alkyl may additionally be monosubstituted by hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyl, or C₁₋₃-alkyloxy, particularly hydroxy,hydroxymethyl, methyl, or methoxy. Preferred substituents of theabovementioned phenyl or pyridyl groups are selected from among F, Cl,Br, I, cyano, C₁₋₄-alkyl, C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl,hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino,aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, and di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, whilea phenyl group may also be monosubstituted by nitro.

Particularly preferred definitions of the groups R¹ and/or R² areselected from among H, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, tetrahydropyran-3, or -4-yl,tetrahydropyranyl-C₁₋₃-alkyl, piperidin-3-yl or -4-yl,N—(C₁₋₄-alkyl)-piperidin-3-yl or -4-yl, piperidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-piperidinyl-C₁₋₃-alkyl, phenyl, pyridyl,phenyl-C₁₋₃-alkyl, pyridyl-C₁₋₃-alkyl, hydroxy-C₂₋₄-alkyl,C₁₋₄-alkoxy-C₂₋₄-alkyl, amino-C₂₋₄-alkyl, C₁₋₄-alkyl-amino-C₂₋₄-alkyl,and di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl, while cycloalkyl rings may bemono-, di-, or trisubstituted by substituents selected from hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyl, or C₁₋₃-alkyloxy, particularly hydroxy,hydroxymethyl, methyl, and methoxy, and C₂₋₄-alkyl bridges in thedefinitions hydroxy-C₂₋₄-alkyl and C₁₋₄-alkoxy-C₂₋₄-alkyl mayadditionally be monosubstituted by hydroxy, hydroxy-C₁₋₃-alkyl,C₁₋₃-alkyl, or C₁₋₃-alkyloxy, particularly hydroxy, hydroxymethyl,methyl, or methoxy, and alkyl groups may be mono- or polysubstituted byF and/or monosubstituted by Cl.

Particularly preferred definitions of the groups R¹ and/or R² are alsoselected from among H, C₁₋₄-alkyl, C₃₋₅-alkenyl, C₃₋₅-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-C₂₋₃-alkyl,pyridyl, and benzyl, while the alkyl, cycloalkyl, or cycloalkylalkylgroup may be mono- or disubstituted by hydroxy, mono- or polysubstitutedby F or monosubstituted by Br, Cl, or CN, and one of the groups R¹ andR² may also represent H.

Most particularly preferred groups R¹ and/or R² are selected from amongH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, propen-3-yl,propin-3-yl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl, phenylmethyl,pyridylmethyl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl,piperidin-4-yl, N—(C₁₋₄-alkyl)-piperidin-4-yl, piperidin-4-ylmethyl,N—(C₁₋₄-alkyl)-piperidin-4-ylmethyl, while the abovementioned ethyl,propyl, and butyl groups may be monosubstituted by amino, methylamino,or dimethylamino, or mono- or disubstituted by hydroxy, methoxy, orethoxy, and the abovementioned cycloalkyl rings may be mono- ordisubstituted by hydroxy, hydroxymethyl, or methyl, and methyl groupsmay be mono- or polysubstituted by fluorine.

Examples of most particularly preferred definitions of the groups R¹and/or R² are methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl,2-methoxyethyl, 3-aminopropyl, propen-3-yl, propin-3-yl, cyclopropyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl,(1-hydroxycyclo-propyl)methyl, phenyl, pyridyl, phenylmethyl,pyridylmethyl, tetrahydropyran-4-yl, N-methylpiperidin-4-yl,N-(methylcarbonyl)piperidin-4-yl, andN-(tert-butyloxycarbonyl)piperidin-4-yl, while hydroxyalkyl groups mayadditionally be substituted by hydroxy, and one of the groups R¹, R² mayalso represent H.

If the substituent R¹ has one of the meanings stated above as beingpreferred, but not H, the substituent R² most particularly preferablydenotes H, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, or2-methoxyethyl.

Particularly preferably at least one of the groups R¹, R², and mostparticularly preferably both groups, have a meaning other than H.

If R¹ and R² form an alkylene bridge, this is preferably a C₃₋₇-alkylenebridge, wherein a —CH₂— group not adjacent to the N atom of the R¹R²N—group may be replaced by —CH═CH—and/or a —CH₂— group which is preferablynot adjacent to the N atom of the R¹R²N— group may be replaced by —O—,—S—, —CO—, —C(═CH₂)—, or —NR¹³—, particularly preferably by —O—, —S— or,—NR¹³—, in such a way that heteroatoms are not directly joined togetherand a group —CO— is not directly linked to the group R¹R²N—, while inthe alkylene bridge defined hereinbefore one or more H atoms may bereplaced by R¹⁴, and the alkylene bridge defined hereinbefore may besubstituted by a carbo- or heterocyclic group Cy in such a way that thebond between the alkylene bridge and the group Cy is made via a singleor double bond, via a common C atom forming a spirocyclic ring system,via two common adjacent C and/or N atoms forming a fused bicyclic ringsystem, or via three or more C and/or N atoms forming a bridged ringsystem.

R¹³ preferably denotes H, C₁₋₆-alkyl, C₁₋₄-alkylcarbonyl, orC₁₋₄-alkyloxycarbonyl. R¹³ particularly preferably denotes H orC₁₋₆-alkyl, particularly H, methyl, ethyl, or propyl.

Preferably also R¹ and R² form an alkylene bridge such that R¹R²N—denotes a group selected from azetidine, pyrrolidine, piperidine,azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine,2,3,4,7-tetrahydro-1H-azepine, and 2,3,6,7-tetrahydro-1H-azepine,piperazine wherein the free imine function is substituted by R¹³,piperidin-4-one, morpholine, and thiomorpholine, particularly selectedfrom pyrrolidine, piperidine, piperidin-4-one, 2,5-dihydro-1H-pyrrole,piperazine, wherein the free imine function is substituted by R¹³,morpholine, and thiomorpholine, while according to the generaldefinition of R¹ and R² one or more H atoms may be replaced by R¹⁴,and/or the abovementioned groups may be substituted by one or twoidentical or different carbo- or heterocyclic groups Cy in a mannerspecified according to the general definition of R¹ and R². Particularlypreferred groups Cy for this are phenyl, C₃₋₇-cycloalkyl,aza-C₄₋₇-cycloalkyl, particularly phenyl, C₃₋₆-cycloalkyl, andcyclo-C₃₋₅-alkyleneimino, as well asN—C₁₋₄-alkyl-(aza-C₄₋₆-cycloalkyl)-, while the cyclic groups Cy may besubstituted as specified.

The alkylene bridge formed by R¹ and R², wherein —CH₂— groups may bereplaced as specified, may be substituted, as described, by one or twoidentical or different carbo- or heterocyclic groups Cy, which may besubstituted as defined hereinbefore.

In the event that the alkylene bridge is linked to a group Cy via asingle bond, Cy is preferably selected from the group consisting ofC₃₋₇-cycloalkyl, cyclo-C₃₋₆-alkyleneimino, piperazinyl, 1H-imidazole,thienyl, and phenyl, particularly C₃₋₆-cycloalkyl, pyrrolidinyl,piperidinyl, and piperazinyl, which may be substituted as specified, andparticularly the N atoms may be substituted by C₁₋₄-alkyl in each case.

In the event that the alkylene bridge is linked to a group Cy via acommon C atom forming a spirocyclic ring system, Cy is preferablyselected from the group consisting of C₃₋₇-cycloalkyl,aza-C₄₋₈-cycloalkyl, oxa-C₄₋₈-cycloalkyl, and2,3-dihydro-1H-quinazolin-4-one, particularly cyclopentyl andcyclohexyl, which may be substituted as specified, and particularly theN atoms may be substituted by C₁₋₄-alkyl in each case.

In the event that the alkylene bridge is linked to a group Cy via twocommon adjacent C and/or N atoms forming a fused bicyclic ring system,Cy is preferably selected from the group consisting of C₄₋₇-cycloalkyl,aza-C₄₋₇-cycloalkyl, phenyl, and thienyl, particularly phenyl andpyrrolidinyl, which may be substituted as specified, and particularlythe N atoms may be substituted by C₁₋₄-alkyl in each case.

In the event that the alkylene bridge is linked to a group Cy via threeor more C and/or N atoms forming a bridged ring system, Cy preferablydenotes C₄₋₈-cycloalkyl or aza-C₄₋₈-cycloalkyl.

Particularly preferably the group

is defined according to one of the following partial formulae

while in the heterocycle formed by the group R^(l)R²N— one or more Hatoms may be replaced by R¹⁴ and/or a H atom may be substituted by Cydefined as C₃₋₇-cycloalkyl, which may be mono- or polysubstituted byR²⁰, particularly by F, hydroxy, C₁₋₃-alkyl, CF₃, C₁₋₃-alkyloxy, OCF₃,or hydroxy-C₁₋₃-alkyl, and the ring connected to the heterocycle formedby the group R¹R²N— may be mono- or polysubstituted at one or more Catoms by R²⁰, and in the case of a phenyl ring may also additionally bemonosubstituted by nitro; and

-   X′ and X″ independently of one another denote a single bond or    C₁₋₃-alkylene and in the event that the group Y is linked to X′ or    X″ via a C atom (of the group Y), may also denote —C₁₋₃-alkylene-O—,    —C₁₋₃-alkylene-NH—, or —C₁₋₃-alkylene-N(C₁₋₃-alkyl), and-   X″ additionally also denotes —O—C₁₋₃-alkylene, —NH—C₁₋₃-alkylene or    —N(C₁₋₃-alkyl)-C₁₋₃-alkylene and in the event that the group Y is    linked to X″ via a C atom (of the group Y), also denotes —NH—,    —N(C₁₋₃-alkyl)-, or —O—,-   while in the meanings given for X′ and X″ hereinbefore in each case    a C atom may be substituted by R¹⁰, preferably by a hydroxy,    ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, and/or C₁₋₄-alkoxy    group, and/or one or two C atoms in each case may be substituted by    one or two identical or different substituents selected from    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl, and    C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenyl    substituents may be joined together, forming a carbocyclic ring    system, and in X′, X″ independently of one another in each case one    or more C atoms may be mono- or polysubstituted by F and/or in each    case one or two C atoms independently of one another may be    monosubstituted by Cl or Br,-   wherein R², R¹⁰, R¹³, R¹⁴, R¹⁸, R²⁰, R²¹, and X have the meanings    given above and hereinafter.

Preferably X′ and X″ independently of one another represent a singlebond or C₁₋₃-alkylene and in the event that the group Y is linked to X′or X″ via a C atom, may also denote —C₁₋₃-alkylene-O—,—C₁₋₃-alkylene-NH—, or —C₁₋₃-alkylene-N(C₁₋₃-alkyl)-, and X″additionally also denotes —O—C₁₋₃-alkylene, —NH—C₁₋₃-alkylene, or—N(C₁₋₃-alkyl)-C₁₋₃-alkylene and in the event that the group Y is linkedto X″ via a C atom, X″ also denotes —NH—, —N(C₁₋₃-alkyl)-, or —O—.Particularly preferably X′ and X″ independently of one another representa single bond or methylene and in the event that the group Y is linkedto X′ or X″ via a C atom, also represent —CH₂—O—, —CH₂—NH—, or—CH₂—N(C₁₋₃-alkyl)-, and in the event that the group Y is linked to X″via a C atom, X″ also denotes —NH—, —N(C₁₋₃-alkyl), or —O—.

In the preferred and particularly preferred meanings of R^(l)R²N— listedabove the following definitions of the substituent R¹⁴ are preferred: F,Cl, Br, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy,ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, carboxy,C₁₋₄-alkoxycarbonyl, hydroxy-carbonyl-C₁₋₃-alkyl,C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino,C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl, amino, C₁₋₄-alkyl-amino,C₃₋₇-cycloalkyl-amino, N—(C₃₋₇-cycloalkyl)-N—(C₁₋₄-alkyl)-amino,di-(C₁₋₄-alkyl)-amino, amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,C₃₋₇-cycloalkyl-amino-C₁₋₃-alkyl,N—(C₃₋₇-cycloalkyl)-N—(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl,aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl, C₃₋₇-cycloalkyl-aminocarbonyl,N—(C₃₋₇-cycloalkyl)-N—(C₁₋₄-alkyl)-aminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, pyridinyloxy, pyridinylamino,pyridinyl-C₁₋₃-alkyl-amino-. In the above meanings of the group R¹⁴ oneor more C atoms may be mono- or polysubstituted by F and/or one or two Catoms independently of one another may be monosubstituted by Cl or Br,and in particular alkyl groups may be mono- or polysubstituted byfluorine.

Most particularly preferred meanings of the substituent R¹⁴ are F, Cl,C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl,C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₄-alkyl-amino-C₁₋₃-alkyl, C₃₋₇-cycloalkyl-amino-C₁₋₃-alkyl,N—(C₃₋₇-cycloalkyl)-N—(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl,aminocarbonyl, and pyridylamino. In the above meanings of the group R¹⁴,one or more C atoms, and particularly alkyl groups, may be mono- orpolysubstituted by fluorine. Thus, preferred meanings of R¹⁴ alsoinclude, for example, —CF₃ and —OCF₃.

If in the heterocycle formed by the group R¹R²N— an H atom is replacedby Cy representing C₃₋₇-cycloalkyl, which may be mono- orpolysubstituted by R²⁰, Cy preferably denotes C₃₋₆-cycloalkyl and R²⁰preferably denotes F, hydroxy, C₁₋₃-alkyl, CF₃, C₁₋₃-alkyloxy, OCF₃, orhydroxy-C₁₋₃-alkyl, particularly F, hydroxy, methyl, methoxy, CF₃, OCF₃,or hydroxymethyl. Particularly preferred meanings of Cy areC₃₋₆-cycloalkyl and 1-hydroxy-C₃₋₅-cycloalkyl.

Most particularly preferably the group

is defined according to one of the following partial formulae

while the group R¹³ has the meanings given hereinbefore and hereinafter,and in the heterocycle formed by the group R¹R²N— one or more H atomsmay be replaced by R¹⁴ and/or an H atom may be replaced by Cyrepresenting C₃₋₆-cycloalkyl, which may be mono- or polysubstituted byR²⁰, particularly by F, hydroxy, C₁₋₃-alkyl, CF₃, C₁₋₃-alkyloxy, OCF₃,or hydroxy-C₁₋₃-alkyl, particularly preferably by F, hydroxy, methyl,methoxy, CF₃, OCF₃, or hydroxymethyl, and the ring connected to theheterocycle formed by the group R¹R²N— may be mono- or polysubstituted,preferably monosubstituted at one or more C atoms by R²⁰, or in the caseof a phenyl ring may also additionally be monosubstituted by nitro;

-   R¹⁴ in each case independently of one another denotes F, Cl,    C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl,    C₁₋₄-alkyloxy, C₁₋₄-alkoxy-C₁₋₃-alkyl, pyridylamino, or    aminocarbonyl, while in each case one or more C atoms, particularly    alkyl groups may additionally be mono- or polysubstituted by F; most    particularly preferably denotes methyl, ethyl, propyl,    trifluoromethyl, hydroxy, hydroxymethyl, 1-hydroxyethyl,    2-hydroxyethyl, 1-hydroxy-1-methyl-ethyl, 1-hydroxycyclopropyl,    methoxy, ethoxy, methoxymethyl, pyridylamino, or aminocarbonyl; and-   R¹³ is as hereinbefore defined, particularly denotes H or    C₁₋₃-alkyl.

Preferably X denotes a C₁₋₆-alkylene bridge, wherein a —CH₂ group notadjacent to the N atom of the R¹R²N— group may be replaced by —CH═CH— or—C≡C— and/or a —CH₂— group not adjacent to the N atom of the R¹R²N groupmay be replaced by —O—, —S—, —CO—, or —NR⁴—, particularly preferably by—O—, —S—, or —NR⁴—, in such a way that in each case two O, S, or N atomsor an O and an S atom are not directly joined together, while R⁴ may beattached to Y, forming a heterocyclic ring system with one another,while the bridge X may be connected to R¹ including the N atom linked toR¹ and X, forming a heterocyclic group, and a C atom not directlyconnected to a heteroatom may be substituted by R¹⁰ and/or one or two Catoms may each be substituted by one or two identical or differentsubstituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl, andC₄₋₇-cycloalkenyl-C₁₋₃-alkyl, particularly C₁₋₄-alkyl, while two alkyland/or alkenyl substituents may be joined together forming a carbocyclicring system, particularly a cyclopropyl, cyclobutyl, or cyclopentylgroup.

In the abovementioned definition of the bridge X two C atoms or a C andan N atom of the alkylene bridge may be joined together by an additionalC₁₋₄-alkylene bridge.

Preferably, in the group X a —CH₂— group directly adjacent to the groupR¹R²N— is not replaced by —O—, —S—, —(SO)—, —(SO₂)—, —CO—, or —NR⁴—.

If in the group X one or two —CH₂— groups independently of one anotherare replaced by —O—, —S—, —(SO)—, —(SO₂)—, —CO—, or —NR⁴—, these groupsare preferably spaced from the R¹R²N— group by an alkylene bridge withat least 2 C atoms.

If in the group X two —CH₂ groups independently of one another arereplaced by —O—, —S—, —(SO)—, —(SO₂)—, —CO—, or —NR⁴—, these groups arepreferably separated from one another by an alkylene bridge with atleast 2 C atoms.

If in the group X a —CH₂— group of the alkylene bridge is replacedaccording to the invention, this —CH₂— group is preferably not directlyconnected to a heteroatom, a double or triple bond.

Preferably the alkylene bridge X, X′, or X″ has no imino groups or atmost only one imino group. The position of the imino group within thealkylene bridge X, X′, or X″ is preferably selected so that no aminalfunction is formed together with the amino group NR¹R² or anotheradjacent amino group, or two N atoms are not adjacent to one another.

Preferably X denotes an unbranched C₁₋₄-alkylene bridge and in the eventthat the group Y is linked to X via a C atom (of the group Y), it alsodenotes —CH₂—CH═CH—, —CH₂—C≡C—, C₂₋₄-alkylenoxy, or C₂₋₄-alkylene-NR⁴—,particularly C₂₋₄-alkylenoxy or C₂₋₄-alkylene-NR⁴—, while R⁴ may beconnected to Y, forming a heterocyclic ring system, while the bridge Xmay be connected to R¹, including the N atom connected to R¹ and X,forming a heterocyclic group, and in X a C atom may be substituted byR¹⁰ and/or one or two C atoms may be substituted in each case by one ortwo identical or different substituents selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,C₄₋₇-cycloalkenyl, and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, particularlyC₁₋₄-alkyl, while two alkyl and/or alkenyl substituents may be joinedtogether, forming a carbocyclic ring system, and in the abovementionedgroups and radicals one or more C atoms may be mono- or polysubstitutedby F and/or one or two C atoms independently of one another may bemonosubstituted by Cl or Br, and R¹, R⁴, and R¹⁰ are as hereinbeforedefined.

Particularly preferably X denotes —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, or—CH₂—CH═CH—CH₂— and in the event that the group Y is linked to X via a Catom (of the group Y), X also denotes —CH₂—CH═CH—, —CH₂—C≡C—,—CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH₂—CH₂—NR⁴—, or —CH₂—CH₂—CH₂—NR⁴—,particularly —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH₂—CH₂—NR⁴—, or—CH₂—CH₂—CH₂—NR⁴—, while R⁴ may be connected to Y forming a heterocyclicring system with one another, while the bridge X may be connected to R¹including the N atom connected to R¹ and X, forming a heterocyclicgroup, and in X a C atom may be substituted by R¹⁰, preferably ahydroxy, ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl and/orC₁₋₄-alkoxy group, and/or one or two C atoms independently of oneanother may each be substituted by one or two identical or differentC₁₋₄-alkyl groups, while two alkyl groups may be joined together,forming a carbocyclic ring system, and in each case one or more C atomsmay be mono- or polysubstituted by F and/or in each case one or two Catoms may independently of one another be monosubstituted by Cl or Br.

Most particularly preferably, in the event that the group Y is linked toX via a C atom (of the group Y), X denotes —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH₂—CH₂—NR⁴—, or—CH₂—CH₂—CH₂—NR⁴—, which may be unsubstituted or substituted asdescribed.

R⁴ has one of the meanings given for R¹⁷, preferably has one of themeanings given for R¹⁶.

Particularly preferred meanings of the substituent R⁴ are H, C₁₋₆-alkyl,and C₃₋₆-alkenyl. Most particularly preferably R⁴ denotes H, methyl, orethyl. If R⁴ is joined to Y, forming a heterocyclic ring system,particularly preferred meanings of R⁴ are C₂₋₆-alkyl and C₂₋₆-alkenyl.

In the event that R⁴ is linked to Y forming a heterocyclic ring systemwith one another, Y preferably denotes phenyl and R⁴ preferably denotesC₂₋₆-alkyl or C₂₋₆-alkenyl. The heterocyclic ring systems preferablyformed are indole, dihydroindole, quinoline, dihydroquinoline,tetrahydroquinoline, and benzoxazole.

The group R⁴ preferably denotes vinyl only when R⁴ is linked to Yforming a heterocyclic ring system.

The substituent R¹⁰ preferably denotes hydroxy, ω-hydroxy-C₁₋₃-alkyl,C₁₋₄-alkoxy, or ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, particularly hydroxy,hydroxymethyl, or methoxy.

The group X preferably does not comprise a carbonyl group.

If in X, X′, or X″ a C atom is substituted, preferred substituents areselected from among the C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy,ω-hydroxy-C₁₋₃-alkyl, ω-(C₁₋₄-alkoxy)-C₁₋₃-alkyl, and CIA-alkoxy groups.Moreover in X, X′, or X″ a C atom may be disubstituted and/or one or twoC atoms may be mono- or disubstituted, while preferred substituents areselected from among C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₇-cycloalkyl, and C₃₋₇-cycloalkyl-C₁₋₃-alkyl, particularlyC₁₋₄-alkyl, and two C₁₋₄-alkyl and/or C₂₋₄-alkenyl substituents may alsobe joined together to form a saturated or monounsaturated carbocyclicring.

If in the group X, X′, or X″ one or more C atoms are substituted by ahydroxy and/or C₁₋₄-alkoxy group, the substituted C atom is preferablynot immediately adjacent to another heteroatom.

Most particularly preferred substituents of one or two C atoms in X, X′,or X″ are selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclopropylmethyl, while two alkyl substituents at a C atom may bejoined together to form a carbocyclic ring.

In the definitions of the substituents of the bridges X, X′, and/or X″and the definitions of the bridges X, X′, and/or X″ themselves mentionedabove and hereinafter, in each case one or more C atoms may additionallybe mono- or polysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br.

If in the group X, X′, or X″ one or more C atoms are substituted asspecified hereinbefore, particularly preferred meanings of X, X′, and X″are selected from among

If Y denotes a fused bicyclic ring system, a preferred definition of thegroup X is —CH₂—, —CH₂—CH₂—, and —CH₂—CH₂—CH₂—, particularly —CH₂— or—CH₂—CH₂—, which may be substituted as specified.

The group Y preferably has a meaning selected from among the bivalentcyclic groups phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, indolyl,dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl,benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, thienyl,benzothienyl, pyrimidinyl, or benzofuranyl, while the abovementionedcyclic groups may be mono- or polysubstituted at one or more C atoms byR²⁰, in the case of a phenyl ring may also additionally bemonosubstituted by nitro, and/or at one or more N atoms may besubstituted by R²¹. R¹ may be connected to Y and/or X may be connectedto Y as specified hereinbefore, while Y preferably denotes phenyl.

If the group Y denotes phenyl or pyridinyl, the bridges X and Z arepreferably connected to the group Y in the para-position.

Particularly preferably the group Y has a meaning selected from amongthe bivalent cyclic groups

in particular Y has one of the following meanings

while the abovementioned cyclic groups may be mono- or polysubstitutedby R²⁰ at one or more C atoms, and in the case of a phenyl ring may alsoadditionally be monosubstituted by nitro, and/or one or more NH groupsmay be substituted by R²¹.

The group Y representing phenyl may be linked to the group X forming acarbo- or heterocyclic group fused to Y. Preferred definitions of thegroups —X-Y— linked to one another are selected from the list comprising

while the abovementioned cyclic groups may be mono- or polysubstitutedby R²⁰ at one or more C atoms, and in the case of a phenyl ring may alsoadditionally be monosubstituted by nitro.

The group Y is preferably unsubstituted or mono- or disubstituted.

Particularly preferred substituents R²⁰ of the group Y are selected fromamong fluorine, chlorine, bromine, cyano, nitro, C₁₋₄-alkyl,C₂₋₆-alkenyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl,trifluoromethoxy, C₂₋₄-alkynyl, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxy-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino, amino,C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, aminocarbonyl,C₁₋₄-alkyl-aminocarbonyl, and di-(C₁₋₄-alkyl)-aminocarbonyl.

Most particularly preferred substituents R²⁰ of the group Y are selectedfrom among fluorine, chlorine, bromine, cyano, C₁₋₃-alkyl, C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, amino, and inthe case of a phenyl ring also nitro.

Most particularly preferably the group Y denotes substituted phenyleneof the partial formula

wherein L¹ has one of the meanings given previously for R²⁰, preferablyF, Cl, Br, I, CH₃, CF₃, OCH₃, OCF₃, methoxycarbonyl, ethoxycarbonyl, CN,amino, or NO₂, or denotes H. Particularly preferred meanings of thesubstituent L¹ are H, Cl, or methoxy.

The bridge Z denotes a single bond or —CR^(7a)R^(7b)—CR^(7c)R^(7d),wherein R^(7a), R^(7b), R^(7c), R^(7d) independently of one anotherpreferably represent H, F, CH₃, or CF₃.

Other preferred definitions of the bridge Z are selected from:

Particularly preferred definitions of the bridge Z are a single bond and—CH₂—CH₂—. Most particularly preferably Z is a single bond.

A preferred meaning of the group A is aryl or heteroaryl.

Preferably the group A is selected from among the cyclic groups phenyl,pyridinyl, or naphthyl, which may be mono- or polysubstituted by R²⁰ atone or more C atoms, and in the case of a phenyl ring may alsoadditionally be monosubstituted by nitro.

If b the value 0, the group A is preferably mono-, di-, ortrisubstituted.

If b has the value 1, the group A is preferably unsubstituted or mono-or disubstituted. If b has the value 1 and the group A ismonosubstituted, the substituent is preferably in the ortho-positionbased on the β-ketoamide group.

Most particularly preferably A is one of the following groups

while these groups may be mono- or polysubstituted by R²⁰ as specified.

Particularly preferred substituents R²⁰ of the group A are selected fromamong fluorine, chlorine, bromine, cyano, C₁₋₄-alkyl, C₂₋₆-alkenyl,hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl,trifluoromethoxy, C₂₋₄-alkynyl, carboxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxy-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino, amino,C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino,aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl, anddi-(C₁₋₄-alkyl)-aminocarbonyl.

Most particularly preferred substituents R²⁰ of the group A are selectedfrom among fluorine, chlorine, bromine, cyano, C₁₋₄-alkyl, C₁₋₄-alkoxy,trifluoromethyl, trifluoromethoxy, carboxy, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkyl-amino, and di-(C₁₋₄-alkyl)-amino.

In the event that b has the value 0, a particularly preferred definitionof the group A is substituted phenyl of the partial formula

wherein:

-   L² has one of the meanings given for R²⁰ or denotes H, preferably F,    Cl, Br, I, CH₃, CF₃, OCH₃, OCF₃, CN, or NO₂,-   L³ has one of the meanings given for R²⁰ or denotes H, preferably F,    Cl, Br, I, CF₃, OCF₃, CN, NO₂, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₁₋₄-alkoxy, C₃₋₇-cycloalkyl-O,    C₃₋₇-cycloalkyl-C₁₋₃-alkoxy, —COO—C₁₋₄-alkyl, or —COOH; particularly    preferably F, Cl, Br, C₁₋₄-alkyl, CF₃, methoxy, OCF₃, CN, or NO₂;    most particularly preferably Cl, Br, CF₃, or NO₂; q has the value 0,    1, or 2,    with the proviso that the phenyl group can be at most    monosubstituted by nitro.

Particularly preferably A is substituted phenyl according to the abovepartial formula, wherein q denotes 1 or 2 and/or at least onesubstituent L² is in the meta-position to the substituent L³.

A particularly preferred definition of the substituent L² is Cl.

Particularly preferred meanings of the substituent L³ are Cl, methoxy,and CF₃.

In the event that b is 1, the group A preferably denotes unsubstitutedphenyl or phenyl substituted by L², while L² is preferably in theortho-position to the β-ketoamide group. L² is as hereinbefore defined.

In the event that b has the value 1, a preferred definition of the groupB is aryl or heteroaryl, which may be substituted as specified.

Preferred definitions of the group B are selected from among phenyl,pyridyl, thienyl, and furanyl. Particularly preferably, the group Bdenotes phenyl. The group B defined as specified may be mono- orpolysubstituted by R²⁰, a phenyl group may additionally also bemonosubstituted by nitro. Preferably the group B is unsubstituted ormono-, di-, or trisubstituted, particularly unsubstituted or mono- ordisubstituted. In the case of a monosubstitution the substituent ispreferably in the ortho-orpara-position, particularly in thepara-position to the group A.

Preferred substituents R²⁰ of the group B are selected from amongfluorine, chlorine, bromine, cyano, nitro, C₁₋₄-alkyl, hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl, trifluoromethoxy,C₂₋₄-alkynyl, carboxy, C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxy-C₁₋₃-alkyl,C₁₋₄-alkoxy-carbonylamino, amino, C₁₋₄-alkyl-amino,di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino, aminocarbonyl,C₁₋₄-alkyl-amino-carbonyl, and di-(C₁₋₄-alkyl)-amino-carbonyl.

Particularly preferred substituents R²⁰ of the group B are selected fromamong fluorine, chlorine, bromine, cyano, CF₃, C₁₋₃-alkyl, C₁₋₄-alkoxy,trifluoromethoxy, and nitro; particularly fluorine, chlorine, bromine,methoxy, CF₃, and trifluoromethoxy.

Most particularly preferred substituents R²⁰ of the group B are selectedfrom among chlorine and methoxy.

The following are preferred definitions of other substituents accordingto the invention: Preferably the substituent R¹³ has one of the meaningsgiven for R¹⁶. Particularly preferably R¹³ denotes H, C₁₋₄-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, ω-hydroxy-C₂₋₃-alkyl,ω-(C₁₋₄-alkoxy)-C₂₋₃-alkyl. Most particularly preferably R¹³ denotes Hor C₁₋₄-alkyl. The alkyl groups mentioned above may be monosubstitutedby Cl or mono- or polysubstituted by F.

Preferred meanings of the substituent R¹⁵ are H, C₁₋₄-alkyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, while, as hereinbeforedefined, in each case one or more C atoms may additionally be mono- orpolysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br. Particularly preferably R¹⁵ denotes H, methyl, ethyl, propyl, orbutyl.

The substituent R¹⁶ preferably denotes H, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, ω-hydroxy-C₂₋₃-alkyl, orω-(C₁₋₄-alkoxy)-C₂₋₃-alkyl, while, as hereinbefore defined, in each caseone or more C atoms may additionally be mono- or polysubstituted by Fand/or in each case one or two C atoms independently of one another mayadditionally be monosubstituted by Cl or Br. Particularly preferably R¹⁶denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl, or C₃₋₆-cycloalkyl-C₁₋₃-alkyl.

Preferably the substituent R¹⁷ has one of the meanings given for R¹⁶ aspreferred meanings or denotes phenyl, phenyl-C₁₋₃-alkyl, pyridinyl, orC₁₋₄-alkylcarbonyl. Particularly preferably R¹⁷ has one of the meaningsgiven for R¹⁶ as preferred meanings.

The substituent R²⁰ preferably denotes halogen, hydroxy, cyano,C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy-C₁₋₄-alkyl, R²²—C₁₋₃-alkyl, or hasone of the meanings given for R²² as preferred meanings, while, ashereinbefore defined, in each case one or more C atoms may additionallybe mono- or polysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br.

Particularly preferred definitions of the group R²⁰ are halogen,hydroxy, cyano, C₁₋₄-alkyl, C₃₋₇-cycloalkyl, and C₁₋₄-alkoxy, while, ashereinbefore defined, in each case one or more C atoms may additionallybe mono- or polysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br. Most particularly preferably R²⁰ denotes F, Cl, Br, I, OH, cyano,methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy,isopropoxy, methoxycarbonyl, ethoxycarbonyl, or amino.

The substituent R²² preferably denotes C₁₋₄-alkoxy, C₁₋₄-alkylthio,carboxy, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,C₁₋₄-alkyl-sulfonyl, C₁₋₄-alkyl-sulfinyl, C₁₋₄-alkyl-sulfonylamino,amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,C₁₋₄-alkyl-carbonyl-amino, hydroxy-C₁₋₃-alkylaminocarbonyl,aminocarbonyl amino, or C₁₋₄-alkylaminocarbonyl-amino, while, ashereinbefore defined, in each case one or more C atoms may additionallybe mono- or polysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br.

Preferred definitions of the group R²¹ are C₁₋₄-alkyl,C₁₋₄-alkylcarbonyl, C₁₋₄-alkylsulfonyl, —SO₂—NH₂, —SO₂—NH—C₁₋₃-alkyl,—SO₂—N(C₁₋₃-alkyl)₂, and cyclo-C₃₋₆-alkyleneimino-sulfonyl, while, ashereinbefore defined, in each case one or more C atoms may additionallybe mono- or polysubstituted by F and/or in each case one or two C atomsindependently of one another may additionally be monosubstituted by Clor Br.

Most particularly preferred meanings of R²¹ are H, C₁₋₄-alkyl,C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, particularly H and C₁₋₃-alkyl.

Cy preferably denotes a C₃₋₇-cycloalkyl, particularly a C₃₋₆-cycloalkylgroup, a C₅₋₇-cycloalkenyl group, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, a phenyl ring to which aC₅₋₇-cycloalkyl or aza-C₄₋₇-cycloalkyl group is fused, aryl orheteroaryl, while aryl or heteroaryl preferably denotes a monocyclic orfused bicyclic ring system, and the abovementioned cyclic groups may bemono- or polysubstituted by R²⁰ at one or more C atoms, in the case of aphenyl group may also additionally be monosubstituted by nitro, and/orone or more NH groups may be substituted by R²¹.

The term aryl preferably denotes phenyl or naphthyl, particularlyphenyl.

The term heteroaryl preferably comprises pyridyl, indolyl, quinolinyl,and benzoxazolyl.

Preferred compounds according to the invention are those wherein one ormore of the groups, radicals, substituents and/or indices have one ofthe meanings specified above as being preferred.

Particularly preferred compounds according to the invention are thosewherein

-   Y has one of the following meanings    while the abovementioned cyclic groups may be mono- or    polysubstituted by R²⁰ at one or more C atoms, and in the case of a    phenyl ring may also additionally be monosubstituted by nitro,    and/or-   A denotes phenyl or pyridyl, which may be mono- or polysubstituted    by R²⁰, and may also additionally be monosubstituted by nitro,    and/or-   B denotes phenyl which may be mono- or polysubstituted by R²⁰, and    may also additionally be monosubstituted by nitro, and/or-   b has the value 0 or 1.

Most particularly preferred are those compounds according to theinvention wherein A, B, b, X, Y, Z, R¹, R², R³, R^(5a), and R^(5b)independently of one another have one or more of the preferred meaningsmentioned above.

Preferred groups of compounds according to this invention can bedescribed by the following formulae, particularly I.a, I.b, and I.c:

while the bridges X appearing in formulae I.a to I.j representing —CH₂—,—CH₂—CH₂—, and —CH₂—CH₂—O— may have one or two substituentsindependently of one another selected from among C₁₋₃-alkyl andC₃₋₅-cycloalkyl, while two alkyl substituents may be joined together,forming a C₃₋₆-cycloalkyl group; particularly preferably, theabove-mentioned bridges X, particularly representing —CH₂—, may have oneor two methyl substituents, while two methyl substituents may be joinedtogether to form a cyclopropyl group; and

-   L¹, L², L³, R¹, R², R³, R^(5a), R^(5b), and R²⁰ are as hereinbefore    defined and substituents occurring several times may have the same    or different meanings; particularly-   R¹ and R² independently of one another denote Hd C₁₋₆-alkyl,    C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, tetrahydropyran-3 or    -4-yl, tetrahydropyranyl-C₁₋₃-alkyl, piperidin-3-yl or -4-yl,    N—(C₁₋₄-alkyl)-piperidin-3-yl or -4-yl, piperidinyl-C₁₋₃-alkyl,    N—(C₁₋₄-alkyl)-piperidinyl-Cg ₃-alkyl, phenyl, pyridyl,    phenyl-C₁₋₃-alkyl, pyridyl-C₁₋₃-alkyl, hydroxy-C₂₋₄-alkyl,    C₁₋₄-alkoxy-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,    C₁₋₄-alkyl-amino-C₂₋₄-alkyl, or di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl,    while cycloalkyl rings may be mono-, di-, or trisubstituted by    substituents selected from hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyl,    or C₁₋₃-alkyloxy, particularly hydroxy, hydroxymethyl, methyl, and    methoxy, and C₂₋₄-alkyl bridges in the definitions    hydroxy-C₂₋₄-alkyl and C₁₋₄-alkoxy-C₂₋₄-alkyl may additionally be    monosubstituted by hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkyl, or    C₁₋₃-alkyloxy, particularly hydroxy, hydroxymethyl, methyl, or    methoxy, and alkyl groups may be mono- or polysubstituted by F    and/or monosubstituted by Cl; R¹, R² independently of one another    denote methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl,    2-hydroxy-propyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl,    2-methoxyethyl, 3-amino-propyl, propen-3-yl, propin-3-yl,    cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,    cyclopentylmethyl, (1-hydroxycyclopropyl)methyl, phenyl, pyridyl,    phenylmethyl, pyridylmethyl, tetrahydropyran-4-yl,    N-methyl-piperidin-4-yl, N-(methylcarbonyl)piperidin-4-yl, or    N-(tert-butyloxycarbonyl)-piperidin-4-yl, while hydroxyalkyl groups    may additionally be substituted by hydroxy, and one of the groups R¹    and R² may also represent H, or-   R¹ and R² are joined together such that the group    is defined according to one of the following partial formulae:    while in the heterocycle formed by the group R¹R²N— one or more H    atoms may be replaced by R¹⁴ and/or a H atom may be replaced by Cy    representing C₃₋₆-cycloalkyl, which may be mono- or polysubstituted    by R²⁰, particularly by F, hydroxy, C₁₋₃-alkyl, CF₃, C₁₋₃-alkyloxy,    OCF₃, or hydroxy-C₁₋₃-alkyl, particularly preferably by F, hydroxy,    methyl, methoxy, CF₃, OCF₃, or hydroxymethyl, and-   the ring connected to the heterocycle formed by the group R¹R²N— may    be mono- or polysubstituted, preferably monosubstituted by R²⁰ at    one or more C atoms, and in the case of a phenyl ring may also    additionally be monosubstituted by nitro and-   R³ preferably denotes H or methyl,-   R¹⁴ in each case independently of one another denote F, Cl,    C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl,    C₁₋₄-alkyloxy, C₁₋₄-alkoxy-C₁₋₃-alkyl, pyridylamino, or    aminocarbonyl, while in each case one or more C atoms may    additionally be mono- or polysubstituted by F or in each case a C    atom may be monosubstituted by Cl; most particularly preferably    denotes methyl, ethyl, propyl, trifluoromethyl, hydroxy,    hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,    1-hydroxy-1-methyl-ethyl, methoxy, ethoxy, methoxymethyl,    pyridylamino, or aminocarbonyl; and-   R¹³ denotes H, C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, or    C₁₋₄-alkyloxycarbonyl; particularly preferably denotes H or    C₁₋₃-alkyl; and-   Q denotes CH or N, particularly denotes CH, while CH may be    substituted by R²⁰,-   L¹, L², and L³ in each case independently of one another have one of    the meanings given previously for R²⁰, preferably denote fluorine,    chlorine, bromine, cyano, C₁₋₃-alkyl, C₁₋₃-alkoxy, trifluoromethyl,    trifluoromethoxy, or nitro,-   p has the value 0 or 1,-   r and s in each case independently of one another have the value 0,    1, 2, or 3, preferably 0, 1, or 2, particularly preferably 0 or 1,    and-   Z, R^(5a), R^(5b), and R²⁰ are as hereinbefore defined and    substituents occurring more than once may have the same or different    meanings, and in particular-   Z denotes a single bond or —CH₂—CH₂—, particularly preferably a    single bond,-   R^(5a) and R^(5b) independently of one another denote H, F, Cl,    methyl or ethyl, particularly preferably H,-   R²⁰ in each case independently of one another preferably denote    fluorine, chlorine, bromine, cyano, C₁₋₄-alkyl, C₂₋₆-alkenyl,    hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl,    trifluoromethoxy, C₂₋₄-alkynyl, carboxy, C₁₋₄-alkoxycarbonyl,    C₁₋₄-alkoxy-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonylamino, amino,    C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino, cyclo-C₃₋₆-alkyleneimino,    aminocarbonyl, C₁₋₄-alkyl-amino-carbonyl and    di-(C₁₋₄-alkyl)-aminocarbonyl,    -   particularly preferably R²⁰ is selected from fluorine, chlorine,        bromine, cyano, nitro, C₁₋₄-alkyl, hydroxy,        ω-hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, trifluoromethyl,        trifluoromethoxy, C₂₋₄-alkynyl, carboxy, C₁₋₄-alkoxycarbonyl,        and C₁₋₄-alkoxy-C₁₋₃-alkyl.

The compounds listed in the experimental section are preferred accordingto the invention. Some particularly preferred compounds are shown below:

Some expressions used hereinbefore and below to describe the compoundsaccording to the invention will now be defined more fully.

The term halogen denotes an atom selected from among F, Cl, Br, and I,particularly F, Cl, and Br.

The term C_(1-n)-alkyl, where n has a value of 3 to 8, denotes asaturated, branched or unbranched hydrocarbon group with I to n C atoms.Examples of such groups include methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,tert-pentyl, n-hexyl, isohexyl, etc.

The term C_(1-n)-alkylene, where n may have a value of 1 to 8, denotes asaturated, branched or unbranched hydrocarbon bridge with 1 to n Catoms. Examples of such groups include methylene (—CH₂—), ethylene(—CH₂—CH₂—), 1-methylethylene (—CH(CH₃)—CH₂—), 1,1-dimethylethylene(—C(CH₃)₂—CH₂—), n-prop-1,3-ylene (—CH₂—CH₂—CH₂—),1-methylprop-1,3-ylene (—CH(CH₃)—CH₂—CH₂—), 2-methylprop-1,3-ylene(—CH₂—CH(CH₃)—CH₂—), etc., as well as the correspondingmirror-symmetrical forms.

The term C_(2-n)-alkenyl, where n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and atleast one C═C-double bond. Examples of such groups include vinyl,1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl etc.

The term C_(2-n)-alkynyl, where n has a value of 3 to 6, denotes abranched or unbranched hydrocarbon group with 2 to n C atoms and a C≡Ctriple bond. Examples of such groups include ethynyl, 1-propynyl,2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl,2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, etc.

The term C_(1-n)-alkoxy denotes a C_(1-n)-alkyl-O— group, whereinC_(1-n)-alkyl is defined as above. Examples of such groups includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy,isohexoxy etc.

The term C_(1-n)-alkylthio denotes a C_(1-n)-alkyl-S— group, whereinC_(1-n)-alkyl is defined as above. Examples of such groups includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio,isopentylthio, neopentylthio, tert-pentylthio, n-hexylthio,isohexylthio, etc.

The term C_(1-n)-alkylcarbonyl denotes a C_(1-n)-alkyl —C(═O)— group,wherein C_(1-n)-alkyl is defined as above. Examples of such groupsinclude methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl,neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl,isohexylcarbonyl, etc.

The term C_(3-n)-cycloalkyl denotes a saturated mono-, bi-, tri-, orspirocarbocyclic, preferably monocarbocyclic group with 3 to n C atoms.Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl,bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl,adamantyl, etc.

The term C_(5-n)-cycloalkenyl denotes a monounsaturated mono-, bi-,tri-, or spirocarbocyclic group with 5 to n C atoms. Examples of suchgroups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,cyclononenyl, etc.

The term C_(3-n)-cycloalkylcarbonyl denotes a C_(3-n)-cycloalkyl-C(═O)group, wherein C_(3-n)-cycloalkyl is as hereinbefore defined.

The term aryl denotes a carbocyclic, aromatic ring system, such as, forexample, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl,fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. Aparticularly preferred meaning of “aryl” is phenyl.

The term cyclo-C₃₋₇-alkyleneimino denotes a 4- to 7-membered ring whichcomprises 3 to 7 methylene units as well as an imino group, while thebond to the residue of the molecule is made via the imino group.

The term cyclo-C₃₋₇-alkyleneimino-carbonyl denotes acyclo-C₃₋₇-alkyleneimino ring as hereinbefore defined which is linked toa carbonyl group via the imino group.

The term heteroaryl used in this application denotes a heterocyclic,aromatic ring system which comprises in addition to at least one C atomone or more heteroatoms selected from N, O and/or S. Examples of suchgroups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl,pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl(thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl,benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl,quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The termheteroaryl also comprises the partially hydrogenated heterocyclic,aromatic ring systems, particularly those listed above. Examples of suchpartially hydrogenated ring systems are 2,3-dihydrobenzofuranyl,pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl,etc. Particularly preferably heteroaryl denotes a heteroaromatic mono-or bicyclic ring system.

Terms such as C₃₋₇-cycloalkyl-C_(1-n)-alkyl, aryl-C_(1-n)-alkyl,heteroaryl-C_(1-n)-alkyl, etc. refer to C_(1-n)-alkyl, as defined above,which is substituted with a C₃₋₇-cycloalkyl, aryl or heteroaryl group.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “unsaturated”, for example, in “unsaturated carbocyclic group”or “unsaturated heterocyclic group”, as used particularly in thedefinition of the group Cy, comprises, in addition to the mono- orpolyunsaturated groups, the corresponding totally unsaturated groups,but particularly the mono- and diunsaturated groups.

The expression “optionally substituted” used in this applicationindicates that the group thus designated is either unsubstituted ormono- or polysubstituted by the substituents specified. If the group inquestion is polysubstituted, the substituents may be identical ordifferent.

The style used hereinbefore and hereinafter, according to which in acyclic group a bond of a substituent is shown towards the centre of thiscyclic group, unless otherwise stated, indicates that this substituentmay be bound to any free position of the cyclic group carrying an Hatom.

Thus in the example

the substituent R²⁰ where s is 1 may be bound to any of the freepositions of the phenyl ring; where s is 2, selected substituents R²⁰may differently from one another be bound to different free positions ofthe phenyl ring.

The H atom of any carboxy group present or an H atom bound to an N atom(imino or amino group) may in each case be replaced by a group which canbe cleaved in vivo. By a group which can be cleaved in vivo from an Natom is meant, for example, a hydroxy group, an acyl group such as thebenzoyl or pyridinoyl group or a C₁₋₁₆-alkanoyl group such as theformyl, acetyl, propionyl, butanoyl, pentanoyl, or hexanoyl group, anallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl group such as themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl, or hexadecyloxycarbonyl group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl, or phenylpropoxycarbonyl group, aC₁₋₃-alkylsulfonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl, orR_(e)CO—O—(R_(f)CR_(g))—O—CO— group wherein R_(e) denotes a C₁₋₈-alkyl,C₅₋₇-cycloalkyl, phenyl, or phenyl-C₁₋₃-alkyl group, R_(f) denotes ahydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl, or phenyl group, and R_(g)denotes a hydrogen atom or a C₁₋₃-alkyl group, while the phthalimidogroup is an additional possibility for an amino group, and theabovementioned ester groups may also be used as a group which can beconverted in vivo into a carboxy group.

The residues and substituents described above may be mono- orpolysubstituted by fluorine as described. Preferred fluorinated alkylgroups are fluoromethyl, difluoromethyl, and trifluoromethyl. Preferredfluorinated alkoxy groups are fluoromethoxy, difluoromethoxy, andtrifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonylgroups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.

The compounds of general formula I according to the invention may haveacid groups, predominantly carboxyl groups, and/or basic groups such as,e.g., amino functions. Compounds of general formula I may therefore bepresent as internal salts, as salts with pharmaceutically useableinorganic acids such as hydrochloric acid, sulfuric acid, phosphoricacid, sulfonic acid, or organic acids (such as, for example, maleicacid, fumaric acid, citric acid, tartaric acid, or acetic acid) or assalts with pharmaceutically useable bases such as alkali or alkalineearth metal hydroxides or carbonates, zinc or ammonium hydroxides ororganic amines such as, e.g., diethylamine, triethylamine,triethanolamine inter alia.

The compounds according to the invention may be obtained using methodsof synthesis which are known in principle. Preferably the compounds areobtained analogously to the methods of preparation explained more fullyhereinafter, which are also an object of this invention. Theabbreviations used hereinafter are defined in the introduction to theexperimental section or are already familiar to those skilled in theart.

If the starting materials or intermediate products listed below containgroups R¹, R², R³, X, Y, Z, A, or B with amine functions, these arepreferably used in protected form, for example, with a Boc, Fmoc, or Cbzprotective group, and liberated at the end of the reactions usingstandard methods.

Compounds of formula I according to the invention are obtained accordingto Synthesis Plan A by reacting an amine of formula A1 with a carboxylicacid or a carboxylic acid derivative of formula A2 using amide synthesismethods known in the art. In the carboxylic acid derivative A2 the groupM preferably has a meaning selected from OH, Cl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, C₁₋₆-alkyl-COO, etc.

Preferably the carboxylic acid compound of formula A2 (M is OH) isreacted with at least one peptide coupling reagent, such as, forexample, TBTU, in a solvent or mixture of solvents and then the reactionmixture is further reacted with the amine compound of formula A1, whilethe minimum of one base is added to the reaction mixture before and/orafter the reaction of the carboxylic acid compound with TBTU. Thepeptide coupling reagent, such as TBTU, is advantageously used in anequimolar amount or in an excess relative to the carboxylic acid A2,preferably from equimolar to a 50 mol % excess. Alternatively thereaction may also be carried out in the presence of an amount of HOBtwhich is equimolar to the TBTU. Advantageously the carboxylic acid offormula A2 is used with TBTU and then this reaction mixture is used withthe amine compound of formula A1 in a molar ratio of the carboxylic acidcompound of formula A2:amine compound of formula A1:TBTU:base of1±0.25:1±0.25:1±0.25:1 to 4.

Instead of a carboxylic acid it is also possible to use thecorresponding activated carboxylic acid derivatives, such as, forexample, esters, orthoesters, or carboxylic acid chlorides oranhydrides.

Suitable bases are, in particular, tertiary amines such as triethylamineor Hünig base as well as alkali metal carbonates, for example, potassiumcarbonate. The reactions take place in a suitable solvent or mixture ofsolvents, while DMF and/or THF is preferably used. The carboxylic acidor the carboxylic acid derivative (A2) and the amine (A1) are preferablyused in a molar ratio of 1.5:1 to 1:1.5. The reaction is advantageouslycarried out over a period of from 1 to 24 hours in a temperature rangefrom 0° C. to 120° C., preferably 20° C. to 80° C.

If activation of the carboxylic acid compound A2 (M is OH) is desired,this can advantageously be done using a mixed anhydride. The mixedanhydride of the carboxylic acid A2 in question is preferably preparedby reacting the carboxylic acid with an excess of alkyl chloroformate,preferably isopropyl chloroformate, in a molar ratio of 1:1 to 1:1.2.Suitable bases are preferably tertiary amines, for example,N-methylmorpholines, which are used in an equimolar amount to the alkylchloroformate in question.

The reaction is carried out in a suitable solvent such as THF attemperatures between −20° C. and 20° C., particularly −15° C. to 0° C.,and takes place over a period of 10 to 2400 minutes.

The mixed anhydride thus obtained is preferably reacted with an aminecompound (A1) without further purification. The amine compound (A1) isused in an excess relative to the carboxylic acid derivative (A2) inquestion, preferably in a 5-10 mol % excess. The reaction is carriedout, for example, at 0° C. to 60° C. over a period of 1 to 4 hours.

Alternatively compounds of formula I according to the invention may beobtained according to Synthesis Plan B1 by hydrolysis of the triple bondof the propynoic acid amides of formula B1. The hydrolysis of thepropynoic acid amides to form the corresponding β-ketoamide is carriedout by the addition of an acid or base and optionally in the presence ofan activating nucleophile. Suitable acids for this purpose areparticularly strong inorganic or organic acids, such as, for example,hydrochloric acid, sulfuric acid, acetic acid, formic acid, oxalic acid,methanesulfonic acid, or trifluoromethanesulfonic acid. Suitable basesare particularly alkali metal hydroxides, carbonates, or acetates, suchas, for example, potassium hydroxide, sodium hydroxide, lithiumhydroxide, sodium acetate, or potassium carbonate, or aqueous solutionsof secondary or tertiary amines, such as, for example, triethylamine,piperidine, morpholine, diisopropylethylamine, or diethylamine.

The acid or base is advantageously used in a molar excess compared withthe propynoic acid amide.

Examples of suitable activating nucleophiles include in particularsecondary amines, such as, for example, piperidine, morpholine, ordiethylamines or thiols, such as, for example, ethanethiol orthiophenol, or phosphines such as, for example, triphenylphosphine ortributylphosphine.

The reaction is advantageously carried out in a suitable solvent ormixture of solvents, possibly in alcohols, such as, for example, inethanol, or in acetone, dimethylformamide, dimethylsulfoxide, oracetonitrile, optionally in each case with the addition of small amountsof water, particularly less than or equal to 10 vol-% based on thevolume of solvent, at temperatures between 20° C. and 120° C.,preferably in the region of the boiling temperature of the solvent.Suitable reaction times are usually in the range from 1 to 24 hours.

Compounds of formula B1 may be obtained by reacting an amine compound ofgeneral formula B2 with a propynoic acid compound of general formula B3in an organic solvent such as, for example, DMF, THF, dioxane,acetonitrile, or toluene in the presence of a base such as, for example,triethylamine and activating reagents such as, for example, CDI, TBTU,or DCC. Instead of the compound B3 it is also possible to use thecarboxylic acid chloride or a mixed anhydride of compound B3. The amidelinking process described in connection with Synthesis Plan A may alsobe used here.

A compound of general formula B3 may also be prepared by reacting acompound of general formula B5 in an organic solvent such as, forexample, dioxane, ethanol, or THF, with or without the addition ofwater, with a base such as potassium tert-butoxide, sodium hydroxide, orsodium ethoxide at temperatures from 0° C. to 150° C. However, it isalso possible for this reaction to react a compound of general formulaB5 with pyridine or quinoline at temperatures from 0° C. to 150° C. Acompound of general formula B5 is obtained by brominating a compound ofgeneral formula B4 in a solvent such as, for example, carbontetrachloride at temperatures between −20° C. to 100° C., preferably attemperatures between 0° C. and ambient temperature.

The compounds according to the invention may advantageously also beobtained by the methods described in the following Examples, which mayalso be combined with methods known to the skilled man from theliterature, for example.

Stereoisomeric compounds of formula (I) may chiefly be separated byconventional methods. The diastereomers are separated on the basis oftheir different physico-chemical properties, e.g., by fractionalcrystallization from suitable solvents, by high pressure liquid orcolumn chromatography, using chiral or preferably non-chiral stationaryphases.

Racemates covered by general formula (I) may be separated, for example,by HPLC on suitable chiral stationary phases (e.g., Chiral-AGP orCHIRALPAK® AD). Racemates which contain a basic or acidic function canalso be separated via the diastereomeric, optically active salts whichare produced on reacting with an optically active acid, for example,(+)- or (−)-tartaric acid, (+)- or (−)-diacetyl tartaric acid, (+)- or(−)-monomethyl tartrate, or (+)-camphorsulfonic acid, or an opticallyactive base, for example, with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine, or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula (I) is reacted with one of theabovementioned optically active acids or bases in equimolar amounts in asolvent and the resulting crystalline, diastereomeric, optically activesalts thereof are separated using their different solubilities. Thisreaction may be carried out in any type of solvent provided that it issufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example, in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralized with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.,with dilute hydrochloric acid or aqueous methanesulfonic acid and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R)- or (S)-enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R)- or (S)-configuration.

As already mentioned, the compounds of formula (I) may be converted intothe salts thereof, particularly for pharmaceutical use into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds offormula (I) with inorganic or organic acids. On the other hand, in thecase of acidically bound hydrogen, the compound of formula (I) may alsobe converted by reaction with inorganic bases into physiologically andpharmacologically acceptable salts with alkali or alkaline earth metalcations as counter-ion. The acid addition salts may be prepared, forexample, using hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.Moreover, mixtures of the above mentioned acids may be used. To preparethe alkali and alkaline earth metal salts of the compound of formula (I)with acidically bound hydrogen the alkali and alkaline earth metalhydroxides and hydrides are preferably used, while the hydroxides andhydrides of the alkali metals, particularly of sodium and potassium, arepreferred and sodium and potassium hydroxide are most preferred.

The compounds according to the present invention, including thephysiologically acceptable salts, are effective as antagonists of theMCH receptor, particularly the MCH-1 receptor, and exhibit good affinityin MCH receptor binding studies. Pharmacological test systems forMCH-antagonistic properties are described in the following experimentalsection.

As antagonists of the MCH receptor the compounds according to theinvention are advantageously suitable as pharmaceutical activesubstances for the prevention and/or treatment of symptoms and/ordiseases caused by MCH or causally connected with MCH in some other way.Generally the compounds according to the invention have low toxicity,they are well absorbed by oral route and have good intracerebraltransitivity, particularly brain accessibility.

Therefore, MCH antagonists which contain at least one compound accordingto the invention are particularly suitable in mammals, such as, forexample, rats, mice, guinea pigs, hares, dogs, cats, sheep, horses,pigs, cattle, monkeys, and humans, for the treatment and/or preventionof symptoms and/or diseases which are caused by MCH or are otherwisecausally connected with MCH.

Diseases caused by MCH or otherwise causally connected with MCH areparticularly metabolic disorders, such as, for example, obesity, andeating disorders, such as, for example, bulimia, including bulimianervosa. The indication obesity includes in particular exogenic obesity,hyperinsulinemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity, central obesity. This range of indicationsalso includes cachexia, anorexia, and hyperphagia.

Compounds according to the invention may be particularly suitable forreducing hunger, curbing appetite, controlling eating behaviour and/orinducing a feeling of satiation.

In addition, the diseases caused by MCH or otherwise causally connectedwith MCH also include hyperlipidemia, cellulitis, fatty accumulation,malignant mastocytosis, systemic mastocytosis, emotional disorders,affectivity disorders, depression, anxiety states, reproductivedisorders, sexual disorders, memory disorders, epilepsy, forms ofdementia, and hormonal disorders.

Compounds according to the invention are also suitable as activesubstances for the prevention and/or treatment of other illnesses and/ordisorders, particularly those which accompany obesity, such as, forexample, diabetes, diabetes mellitus, particularly type II diabetes,hyperglycemia, particularly chronic hyperglycemia, complications ofdiabetes including diabetic retinopathy, diabetic neuropathy, diabeticnephropathy, etc., insulin resistance, pathological glucose tolerance,encephalorrhagia, cardiac insufficiency, cardiovascular diseases,particularly arteriosclerosis and high blood pressure, arthritis, andgonitis.

MCH antagonists and formulations according to the invention mayadvantageously be used in combination with a dietary therapy, such as,for example, a dietary diabetes treatment, and exercise.

Another range of indications for which the compounds according to theinvention are advantageously suitable is the prevention and/or treatmentof micturition disorders, such as, for example, urinary incontinence,hyperactive bladder, urgency, nycturia, and enuresis, while thehyperactive bladder and urgency may or may not be connected with benignprostatic hyperplasia.

Generally speaking, the compounds according to the invention arepotentially suitable for preventing and/or treating dependencies, suchas, for example, alcohol and/or nicotine dependency, and/or withdrawalsymptoms, such as, for example, weight gain in smokers coming offnicotine. By “dependency” it is generally meant here an irresistibleurge to take an addictive substance and/or to perform certain actions,particularly in order to either achieve a feeling of wellbeing or toeliminate negative emotions. In particular, the term “dependency” isused here to denote a dependency on an addictive substance. By“withdrawal symptoms” are meant here, in general, symptoms which occuror may occur when addictive substances are withdrawn from patientsdependent on one or more such substances. The compounds according to theinvention are potentially suitable particularly as active substances forreducing or ending tobacco consumption, for the treatment or preventionof a nicotine dependency and/or for the treatment or prevention ofnicotine withdrawal symptoms, for reducing the craving for tobaccoand/or nicotine and generally as an anti-smoking agent. The compoundsaccording to the invention may also be useful for preventing or at leastreducing the weight gain typically seen when smokers are coming offnicotine. The substances may also be suitable as active substances whichprevent or at least reduce the craving for and/or relapse into adependency on addictive substances. The term addictive substances refersparticularly but not exclusively to substances with a psycho-motoractivity, such as narcotics or drugs, particularly alcohol, nicotine,cocaine, amphetamine, opiates, benzodiazepines, and barbiturates.

The dosage required to achieve such an effect is conveniently, byintravenous or sub-cutaneous route, 0.001 to 30 mg/kg of body weight,preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route orby inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30mg/kg of body weight, in each case 1× to 3× daily.

For this purpose, the compounds of formula I prepared according to theinvention may be formulated, optionally in conjunction with other activesubstances as described hereinafter, together with one or more inertconventional carriers and/or diluents, e.g., with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose, or fattysubstances such as hard fat or suitable mixtures thereof, to produceconventional galenic preparations such as plain or coated tablets,capsules, lozenges, powders, granules, solutions, emulsions, syrups,aerosols for inhalation, ointments, or suppositories.

In addition to pharmaceutical compositions the invention also includescompositions containing at least one amide compound according to theinvention and/or a salt according to the invention optionally togetherwith one or more physiologically acceptable excipients. Suchcompositions may also be, for example, foodstuffs which may be solid orliquid, in which the compound according to the invention isincorporated.

For the above mentioned combinations it is possible to use as additionalactive substances particularly those which, for example, potentiate thetherapeutic effect of an MCH antagonist according to the invention interms of one of the indications mentioned above and/or which make itpossible to reduce the dosage of an MCH antagonist according to theinvention. Preferably one or more additional active substances areselected from among active substances for the treatment of diabetes,active substances for the treatment of diabetic complications, activesubstances for the treatment of obesity, preferably other than MCHantagonists, active substances for the treatment of high blood pressure,active substances for the treatment of hyperlipidemia, includingarteriosclerosis, active substances for the treatment of dyslipidemia,including arteriosclerosis, active substances for the treatment ofarthritis, active substances for the treatment of anxiety states, andactive substances for the treatment of depression.

The above mentioned categories of active substances will now beexplained in more detail by means of examples.

Examples of active substances for the treatment of diabetes are insulinsensitizers, insulin secretion accelerators, biguanides, insulins,x-glucosidase inhibitors, and 3 adrenoreceptor agonists.

Insulin sensitizers include glitazones, particularly pioglitazone andits salts (preferably hydrochloride), troglitazone, rosiglitazone andits salts (preferably maleate), JTT-501, GI-262570, MCC-555, YM-440,DRF-2593, BM-13-1258, KRP-297, R-119702, and GW-1929.

Insulin secretion accelerators include sulfonylureas, such as, forexample, tolbutamide, chloropropamide, tolazamide, acetohexamide,glyclopyramide and its ammonium salts, glibenclamide, gliclazide, andglimepiride. Further examples of insulin secretion accelerators arerepaglinide, nateglinide, mitiglinide (KAD-1229), and JTT-608.

Biguanides include metformin, buformin, and phenformin.

Insulins include those obtained from animals, particularly cattle orpigs, semisynthetic human insulins which are synthesized enzymaticallyfrom insulin obtained from animals, human insulin obtained by geneticengineering, e.g., from Escherichia coli or yeasts. Moreover, the terminsulin also includes insulin-zinc (containing 0.45 to 0.9 percent byweight of zinc) and protamine-insulin-zinc obtainable from zincchloride, protamine sulfate, and insulin. Insulin may also be obtainedfrom insulin fragments or derivatives (for example INS-1, etc.). Insulinmay also include different kinds, e.g., with regard to the onset timeand duration of effect (“ultra immediate action type”, “immediate actiontype”, “two phase type”, “intermediate type”, “prolonged action type”,etc.), which are selected depending on the pathological condition of thepatient.

α-Glucosidase inhibitors include acarbose, voglibose, miglitol, andemiglitate.

β₃ Adrenoreceptor agonists include AJ-9677, BMS-196085, SB-226552, andAZ40140.

Active substances for the treatment of diabetes other than thosementioned above include ergoset, pramlintide, leptin, BAY-27-9955 aswell as glycogen phosphorylase inhibitors, sorbitol dehydrogenaseinhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidylprotease inhibitors, glipazide, and glyburide.

Active substances for the treatment of diabetic complications include,for example, aldose reductase inhibitors, glycation inhibitors andprotein kinase C inhibitors, DPP-IV blockers, GLP-1 or GLP-2 analogues,and SGLT-2 inhibitors.

Aldose reductase inhibitors are, for example, tolrestat, epalrestat,imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, and AS-3201.

An example of a glycation inhibitor is pimagedine.

Protein Kinase C inhibitors are, for example, NGF and LY-333531.

DPP-IV blockers are, for example, LAF237 (Novartis), MK431 (Merck) aswell as 815541, 823093, and 825964 (all GlaxoSmithkline).

GLP-1 analogues are, for example, liraglutide (NN2211) (NovoNordisk),CJC1131 (Conjuchem), and exenatide (Amylin).

SGLT-2 inhibitors are, for example, AVE-2268 (Aventis) and T-1095(Tanabe, Johnson & Johnson).

Active substances other than those mentioned above for the treatment ofdiabetic complications include alprostadil, thiapride hydrochloride,cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine,and pimagedine (ALT-711).

Active substances for the treatment of obesity, preferably other thanMCH antagonists, include lipase inhibitors and anorectics.

A preferred example of a lipase inhibitor is orlistat.

Examples of preferred anorectics are phentermine, mazindol, fluoxetine,sibutramine, baiamine, (S)-sibutramine, SR-141716, and NGD-95-1.

Active substances other than those mentioned above for the treatment ofobesity include lipstatin.

Moreover for the purposes of this application the active substance groupof anti-obesity active substances also includes the anorectics, of whichthe β₃ agonists, thyromimetic active substances and NPY antagonistsshould be emphasized. The range of substances which may be considered aspreferred anti-obesity or anorectic active substances is indicated bythe following additional list, by way of example: phenylpropanolamine,ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A(hereinafter referred to as CCK-A) agonist, a monoamine reuptakeinhibitor (such as, for example, sibutramine), a sympathomimetic activesubstance, a serotonergic active substance (such as, for example,dexfenfluramine, fenfluramine, a 5-HT2C agonist such as BVT.933 orAPD356), a dopamine antagonist (such as, for example, bromocriptine orpramipexole), a melanocyte-stimulating hormone receptor agonist ormimetic, an analogue of melanocyte-stimulating hormone, a cannabinoidreceptor antagonist (ACOMPLIA® (rimonabant)), an MCH antagonist, the OBprotein (hereinafter referred to as leptin), a leptin analogue, a fattyacid synthase (FAS) antagonist, a leptin receptor agonist, a galanineantagonist, a GI lipase inhibitor or reducer (such as, for example,orlistat). Other anorectics include bombesin agonists,dehydroepiandrosterone or its analogues, glucocorticoid receptoragonists and antagonists, orexin receptor antagonists, urocortin bindingprotein antagonists, agonists of the Glucagon-like Peptide-1 receptor,such as, for example, exendin, AC 2993, CJC-1131, ZP10, or GRT0203Y,DPP-IV inhibitors, and ciliary neurotrophic factors, such as, forexample, axokines. In this context mention should also be made of theforms of therapy which produce weight loss by increasing the fatty acidoxidation in the peripheral tissue, such as, for example, inhibitors ofacetyl-CoA carboxylase.

Active substances for the treatment of high blood pressure includeinhibitors of angiotensin converting enzyme, calcium antagonists,potassium channel openers, and angiotensin II antagonists.

Inhibitors of angiotensin converting enzyme include captopril,enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril,benazepril, cilazapril, temocapril, trandolapril, and manidipine(hydrochloride).

Examples of calcium antagonists are nifedipine, amlodipine, efonidipine,and nicardipine.

Potassium channel openers include levcromakalim, L-27152, AL0671, andNIP-121.

Angiotensin II antagonists include telmisartan, losartan, candesartancilexetil, valsartan, irbesartan, CS-866, and E4177.

Active substances for the treatment of hyperlipidemia, includingarteriosclerosis, include HMG-CoA reductase inhibitors and fibratecompounds.

HMG-CoA reductase inhibitors include pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin,itavastatin, ZD-4522, and their salts.

Fibrate compounds include bezafibrate, clinofibrate, clofibrate, andsimfibrate.

Active substances for the treatment of dyslipidemia, includingarteriosclerosis, include e.g., medicaments which raise the HDL level,such as, e.g., nicotinic acid and derivatives and preparations thereof,such as, e.g., niaspan, as well as agonists of the nicotinic acidreceptor.

Active substances for the treatment of arthritis include NSAIDs(non-steroidal anti-inflammatory drugs), particularly COX-2 inhibitors,such as, for example, meloxicam or ibuprofen.

Active substances for the treatment of anxiety states includechlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam,lorazepam, alprazolam, and fludiazepam.

Active substances for the treatment of depression include fluoxetine,fluvoxamine, imipramine, paroxetine, and sertraline.

The dosage for these active substances is conveniently ⅕ of the lowestnormal recommended dose up to 1/1 of the normal recommended dose.

In another embodiment the invention also relates to the use of at leastone amide compound according to the invention and/or a salt according tothe invention for influencing the eating behaviour of a mammal. This useis particularly based on the fact that compounds according to theinvention may be suitable for reducing hunger, curbing appetite,controlling eating behaviour and/or inducing a feeling of satiety. Theeating behaviour is advantageously influenced so as to reduce foodintake. Therefore, the compounds according to the invention areadvantageously used for reducing body weight. Another use according tothe invention is the prevention of increases in body weight, forexample, in people who had previously taken steps to lose weight and areinterested in maintaining their lower body weight. According to thisembodiment it is preferably a non-therapeutic use. Such anon-therapeutic use might be a cosmetic use, for example, to alter theexternal appearance, or an application to improve general health. Thecompounds according to the invention are preferably usednon-therapeutically for mammals, particularly humans, not suffering fromany diagnosed eating disorders, no diagnosed obesity, bulimia, diabetesand/or no diagnosed micturition disorders, particularly urinaryincontinence. Preferably, the compounds according to the invention aresuitable for non-therapeutic use in people whose BMI (body mass index),defined as their body weight in kilograms divided by their height (inmeters) squared, is below a level of 30, particularly below 25.

The Examples that follow are intended to illustrate the invention.

Preliminary Remarks

As a rule, IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. Unless otherwise stated the R_(f) values weredetermined using ready-made silica gel 60 TLC plates F₂₅₄ (E. Merck,Darmstadt, Item No. 1.05714) without chamber saturation. The R_(f)values obtained under the heading Alox were determined using ready-madealuminum oxide 60 TLC plates F₂₅₄ (E. Merck, Darmstadt, Item No.1.05713) without chamber saturation. The ratios specified for theeluants are based on units by volume of the solvents in question. Theunits by volume specified in the case of NH₃ relate to a concentratedsolution of NH₃ in water. For chromatographic purification, silica gelmade by Messrs Millipore (MATREX™, 35-70 my) is used. Forchromatographic purification, Alox (E. Merck, Darmstadt, standardizedaluminum oxide 90, 63-200 μm, Item No. 1.01097.9050) is used.

The following abbreviations for the eluant mixtures are used hereinafterwhen giving the R_(f) values:

-   (A): silica gel, methylene chloride/methanol/ammonia (9:1:0.01)-   (B): silica gel, methylene chloride/methanol/ammonia (5:1:0.01)-   (C): silica gel, methylene chloride/methanol (9:1)-   (D): silica gel, methylene chloride/methanol/ammonia (9:1:0.1)-   (E): aluminum oxide, methylene chloride/methanol (30:1)

If there is no specific information as to the configuration, it is notclear whether there are pure enantiomers or whether partial or eventotal racemization has taken place.

The following abbreviations are used above and hereinafter:

-   abs. absolute-   Cbz benzyloxycarbonyl-   DMF N,N-dimethylformamide-   EII electron impact ionization-   ether diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   Fmoc 9-fluorenylmethoxycarbonyl-   MeOH methanol-   Ph phenyl-   RT ambient (room) temperature-   TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   THF tetrahydrofuran    Preparation of the Starting Compounds

EXAMPLE I.1 Ethyl 3-biphenyl-4-yl-3-oxopropionate

14.7 g (75.0 mmol) of 4-acetylbiphenyl is dissolved in 150 mL ofdiethylcarbonate. Under protective gas, a total of 6.50 g (150 mmol)sodium hydride in oil (55%) is added batchwise at 0° C. The mixture iskept for 5 minutes at 0° C., then stirred for 2 hours at 80° C. Aftercooling, the mixture is poured onto water and extracted with methylenechloride; the organic phase is washed with water and finally dried oversodium sulfate. The solvent is eliminated, the residue is suspended inwater and neutralized with 1N hydrochloric acid. The aqueous phase isextracted with diethyl ether, the organic phase is dried over sodiumsulfate, and finally the solvent is eliminated. Lastly the residue isrecrystallized from petroleum ether and the product is dried in vacuo at50° C. Yield: 15.3 g (76% of theory); R_(f) value: 0.60 (silica gel,petroleum ether/ethyl acetate=5:2); m.p. 75° C.-77° C.; C₁₇H₁₆O₃; EIImass spectrum: m/z=269 [M+H]⁺.

EXAMPLE II.1 Ethyl 3-(4′-chlorobiphenyl-4-yl)-3-oxopropionate

4.29 g (32.5 mmol) of monoethyl malonate is dissolved in 100 mL of THFand 42.3 mL (67.7 mmol) of butyllithium solution (1.6N in hexane) isadded dropwise at −60° C. The temperature is allowed to come up to −15°C., then the mixture is cooled again to −65° C. and 3.40 g (13.5 mmol)of 4′-chlorobiphenyl-4-carboxylic acid chloride (for preparation seeGazz. Chim. Ital. 1949, 79, 453.) in 30 mL of THF is added dropwise. Themixture is kept for 5 minutes at −65° C., then heated for 2 hours toambient temperature. The mixture is poured onto 50 mL of 1N hydrochloricacid, extracted with 300 mL of diethyl ether, and the organic phase iswashed with saturated sodium hydrogen carbonate solution and water andfinally dried over sodium sulfate. The solvent is eliminated, theresidue is recrystallized from petroleum ether and the product is driedin vacuo. Yield: 3.10 g (76% of theory); R_(f) value: 0.60 (silica gel,petroleum ether/ethyl acetate=5:2); m.p. 45° C.-50° C.; C₁₇H₁₅ClO₃; EIImass spectrum: m/z=303/305 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (II.2) ethyl 3-(3-chlorobiphenyl-4-yl)-3-oxopropionate; and-   (II.3) ethyl 3-(4-methoxyphenyl)-3-oxopropionate.

EXAMPLE III.1 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylamine

III.a: 4-(2-bromoethoxy)-3-chloronitrobenzene

36.6 mL (416 mmol) of 1,2-dibromoethane is dissolved in 200 mL of DMFand 11.5 g (83.3 mmol) of potassium carbonate is added. 7.20 g (41.6mmol) of 2-chloro-4-nitrophenol in 40 mL of DMF is slowly added dropwiseto this mixture. The mixture is stirred for 3 hours at ambienttemperature. The solvent is eliminated, the residue is taken up in ethylacetate and washed with saturated saline solution. The organic phase isdried over sodium sulfate. The solvent is eliminated and the residue ispurified through a silica gel column with a gradient of petroleumether/ethyl acetate (4:1 to 9:1). Yield: 7.9 g (68% of theory); R_(f)value: 0.55 (silica gel, petroleum ether/ethyl acetate=3:1);C₈H₇BrClNO₃.

III.1.b: 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]nitrobenzene

7.80 g (27.8 mmol) of 4-(2-bromoethoxy)-3-chloronitrobenzene (III.1.a)and 10.1 mL (84.0 mmol) of 4-methylpiperidine is dissolved in 100 mL ofmethylene chloride and stirred for 12 hours at ambient temperature. Thenthe mixture is filtered through 400 g of aluminum oxide (activity 2-3)with methylene chloride/methanol 49:1 as eluant. Yield: 6.9 g (83% oftheory); R_(f) value: 0.50 (aluminum oxide, petroleum ether/ethylacetate=3:1); C₁₄H₁₉ClN₂O₃; EII mass spectrum: m/z=299/301 [M+H]⁺.

III.1.c: 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylamine

6.90 g (23.1 mmol) of3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]nitrobenzene (III.1.b) aredissolved in 100 mL of THF and hydrogenated for 8 hours at ambienttemperature at a pressure of 20 psi with hydrogen and 3.0 g of Raneynickel as catalyst. Then the catalyst is filtered off, the solvent iseliminated, and the residue is purified through a silica gel column witha gradient of methylene chloride/methanol (33:1 to 9:1) as eluant.Yield: 3.66 g (59% of theory); R_(f) value: 0.50 (silica gel, methylenechloride/methanol=9:1); C₁₄H₂₁ClN₂O; EII mass spectrum: m/z=269/271[M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (III.2)    4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]-3-methoxyphenylamine;-   (III.3) 4-[2-(4-methylpiperidin-1-yl)ethoxy]-3-methoxyphenylamine;-   (III.4) 3-chloro-4-[2-(morpholin-4-yl)ethoxy]phenylamine;-   (III.5)    3-chloro-4-[2-(N-methylcyclopropylmethylamino)ethoxy]phenylamine;-   (III.6) 3-chloro-4-[2-(4-methoxypiperidin-1-yl)ethoxy]phenylamine;-   (III.7) 3-chloro-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenylamine;    and-   (III.8) 3-chloro-4-[2-(4-hydroxypiperidin-1-yl)ethoxy]phenylamine.

EXAMPLE IV.1 3-chloro-4-(2-diethylaminoethoxy)phenylamine

IV.1.a: 3-chloro-4-(2-diethylaminoethoxy)nitrobenzene

52.0 g (0.30 mol) of 2-chloro-4-nitrophenol is dissolved in 500 mL ofDMF and 165 g (1.20 mol) of potassium carbonate is added batchwise. Themixture is stirred for 30 minutes at ambient temperature. Then 51.6 g(0.30 mol) of 2-diethylaminoethylchloride hydrochloride is added and themixture is stirred for 3 days at ambient temperature. After this time,the mixture is filtered off, the solvent is eliminated, the residue istaken up in ethyl acetate, and washed with water. The organic phase isfiltered through aluminum oxide (activity 2-3) and concentrated byevaporation. Yield: 41.0 g (50% of theory); R_(f) value: 0.60 (silicagel, methylene chloride/methanol/ammonia=9:1:0.01); C₁₂H₁₇ClN₂O₃.

IV.1.b: 3-chloro-4-(2-diethylaminoethoxy)phenylamine

41.0 g (150 mmol) of 3-chloro-4-(2-diethylaminoethoxy)nitrobenzene(IV.1.a) is dissolved in 250 mL of methanol and hydrogenated for 5 hoursat ambient temperature at a pressure of 50 psi with hydrogen and 4.0 gof Raney nickel as catalyst. Then the catalyst is filtered off and thesolvent is eliminated. The residue is recrystallized from petroleumether and dried in vacuo. Yield: 33.0 g (91% of theory); R_(f) value:0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01);C₁₂H₁₉ClN₂O; EII mass spectrum: m/z=243/245 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (IV.2) 4-(2-diethylaminoethoxy)phenylamine;-   (IV.3) 4-(2-diethylaminoethoxy)-3-methoxyphenylamine;-   (IV.4) 4-(2-pyrrolidin-1-ylethoxy)-3-trifluoromethylphenylamine; and-   (IV.5) 4-(3-diethylaminopropoxy)phenylamine.

EXAMPLE V.1 3-methoxycarbonyl-4-(2-pyrrolidin-1-ylethoxy)phenylamine

V.1.a: 3-methoxycarbonyl-4-(2-pyrrolidin-1-ylethoxy)nitrobenzene

3.43 g (29.8 mmol) of 2-pyrrolidin-1-ylethanol is dissolved in 60 mL oftoluene and 575 mg (25.0 mmol) of sodium is added batchwise. The mixtureis heated to 100° C. and then stirred for a further 12 hours at 50° C.After cooling, 5.00 g (22.5 mmol) of methyl 2-chloro-5-nitrobenzoate areadded batchwise and the mixture is stirred for 1 day at ambienttemperature. After this time, the solvent is eliminated, the residue istaken up in methylene chloride and washed with water. The organic phaseis dried over sodium sulfate and concentrated by rotary evaporation.Finally the product is purified through a silica gel column with agradient of methylene chloride/methanol/ammonia (8:2 to 8:2:0.1) aseluant. Yield: 1.65 g (25% of theory); R_(f) value: 0.45 (silica gel,methylene chloride/methanol/ammonia=9:1:0.1); C₁₄H₁₈N₂O₅; EII massspectrum: m/z=295 [M+H]⁺.

V.1.b: 3-methoxycarbonyl-4-(2-pirrolidin-1-ylethoxy)phenylamine

1.65 g (5.61 mmol) of3-methoxycarbonyl-4-(2-pyrrolidin-1-ylethoxy)nitrobenzene (V.1.a) isdissolved in 100 mL of methanol and hydrogenated with hydrogen and 200mg of Raney nickel as catalyst until the reaction is complete. Then thecatalyst is filtered off and the solvent is eliminated. Yield: 1.43 g(97% of theory); R_(f) value: 0.15 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1); C₁₄H₂₀N₂O₃; EII mass spectrum:m/z=265 [M+H]⁺.

EXAMPLE VI.1 3-chloro-4-(2-diethylaminoethyl)phenylamine

VI.1.a: (2-chloro-4-nitrophenyl)acetic acid chloride

8.10 g (37.6 mmol) of (2-chloro-4-nitrophenyl)acetic acid is suspendedin 40 mL of thionyl chloride and refluxed for 2 hours. The product isreacted further without any more purification. Crude yield: 8.80 g (100%of theory); C₈H₅Cl₂NO₃.

VI.1.b: 2-(2-chloro-4-nitrophenyl)-N,N-diethylacetamide

5.67 mL (54.0 mmol) of diethylamine is dissolved in 50 mL of ethylacetate and 3.20 g (13.7 mmol) of (2-chloro-4-nitrophenyl)acetic acidchloride (VI.1.a) in 50 mL of ethyl acetate is slowly added dropwise at0° C. Then the mixture is stirred for another 2 hours at ambienttemperature. After this time, some more ethyl acetate is added and themixture is washed twice with water and twice with saturated salinesolution. The organic phase is dried over sodium sulfate, the solvent iseliminated and the residue is dried in vacuo. Yield: 3.70 g (100% oftheory); R_(f) value: 0.45 (silica gel, petroleum ether/ethylacetate=1:1); C₁₂H₁₅ClN₂O₃; EII mass spectrum: m/z=271/273 [M+H]⁺.

VI.1.c: [2-(2-chloro-4-nitrophenyl)ethyl]diethylamine

65.0 mL (65.0 mmol) of a 1M borane-THF solution is added dropwise atambient temperature to a solution of 3.70 g (13.7 mmol)2-(2-chloro-4-nitrophenyl)-N,N-diethylacetamide (VI.1.b) in 130 mL ofTHF and the mixture is stirred for 4 hours. Then the reaction mixture isevaporated down and the residue is combined with 15 mL of methanol and15 mL of dilute hydrochloric acid. The mixture is then stirred for 15minutes at 100° C., cooled, and diluted with water. Then the mixture ismade alkaline with sodium carbonate solution and extracted twice withethyl acetate. The combined organic phases are extracted twice withwater and once with saturated saline solution and dried over sodiumsulfate. The purification is carried out by column chromatography onAlox (neutral, activity II-III) with petroleum ether/ethyl acetate (4:1)as eluant. Yield: 2.10 g (60% of theory); R_(f) value: 0.65 (Alox,petroleum ether/ethyl acetate=3:1); C₁₂H₁₇ClN₂O₂.

VI.1.d: 3-chloro-4-(2-diethylaminoethyl)phenylamine

2.00 g (7.79 mmol) of [2-(2-chloro-4-nitrophenyl)ethyl]diethylamine(VI.1.c) is dissolved in 50 mL of THF and hydrogenated for 2.5 hours atambient temperature at a pressure of 25 psi with hydrogen and 0.8 g ofRaney nickel as catalyst. Then the catalyst is filtered off and thesolvent is eliminated. Yield: 1.80 g (100% of theory); R_(f) value: 0.45(Alox, petroleum ether/ethyl acetate=1:1); C₁₂H₁₉CIN₂; EII massspectrum: m/z=227/229 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (VI.2) 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine;-   (VI.3) 3-chloro-4-[2-(4-methoxypiperidin-1-yl)ethyl]phenylamine;-   (VI.4) 3-chloro-4-[2-(N-methylisopropylamino)ethyl]phenylamine;-   (VI.5)    3-chloro-4-{2-[4-(morpholin-4-yl)piperidin-1-yl]ethyl}phenylamine;-   (VI.6)    3-chloro-4-[2-(4-hydroxy-4-trifluoromethylpiperidin-1-yl)ethyl]phenylamine;-   (VI.7)    3-chloro-4-[2-(4-tert-butoxycarbonylaminopiperidin-1-yl)ethyl]phenylamine;-   (VI.8) 3-chloro-4-[2-(N-ethyl-2-hydroxyethylamino)ethyl]phenylamine;    and-   (VI.9) 2-amino-5-(piperidin-1-ylmethyl)pyridine.

EXAMPLE VII.1 5-amino-1-(2-pyrrolidin-1-ylethyl)-1H-indole

VII.1.a: 5-nitro-1-(2-pyrrolidin-1-ylethyl)-1H-indole

A reaction mixture of 16.2 g (100 mmol) of 5-nitroindole, 35.0 g (206mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride, and 51.0 g (369mmol) of potassium carbonate in 500 mL of DMF is stirred for 48 hours atambient temperature and then filtered. The filtrate is evaporated down,and the residue is dissolved in dichloromethane and dried over sodiumsulfate. The drying agent is filtered off and the filtrate evaporateddown. Yield: 25 g (96% of theory); R_(f) value: 0.65 (silica gel,dichloromethane/methanol/ammonia=9:1:0.1); C₁₄H₁₇N₃O₂; EII massspectrum: m/z=260 [M+H]⁺.

VII.1.b: 5-amino-1-(2-pyrrolidin-1-ylethyl)-1H-indole

Prepared analogously to Example VI.1.d from 27.0 g (104 mmol) of5-nitro-1-(2-pyrrolidin-1-ylethyl)-1H-indole (VII.1.a) in THF assolvent. Yield: 23.2 g (97% of theory); R_(f) value: 0.50 (silica gel,dichloromethane/methanol/ammonia=9:1:0.1); C₁₄H₁₉N₃; EII mass spectrum:m/z=230 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (VII.2) 5-amino-1-(2-piperidin-1-ylethyl)-1H-indole;-   (VII.3) 5-amino-1-(2-azepan-1-ylethyl)-1H-indole;-   (VII.4) 5-amino-1-(2-diisoproylaminoethyl)-1H-indole;-   (VII.5) 5-amino-1-{2-[bis-(2-methoxyethyl)amino]ethyl}-1H-indole;-   (VII.6) 5-amino-1-[2-(N-benzylethylamino)ethyl]-1H-indole; and-   (VII.7) 5-amino-1-(2-diethylaminoethyl)-1H-indole.

EXAMPLE VIII.1 2-(pyrrolidin-1-ylmethyl)benzoxazol-6-ylamine

VIII.1.a: 2-chloromethyl-6-nitrobenzoxazole

A reaction mixture of 12.0 g (77.9 mmol) of 2-amino-4-nitrophenol and10.5 mL (77.9 mmol) of 2-chloro-1.1.1-trimethoxyethane in 110 mL ofethanol is stirred for 3 hours at 80° C. After this time, the mixture ispoured onto water and the precipitate formed is filtered off. Thefiltrate is washed with water and dried at 80° C. Yield: 14.2 g (86% oftheory); C₈H₅ClN₂O₃; EII mass spectrum: m/z=213/215 [M+H]⁺.

VIII.1.b: 6-nitro-2-(pyrrolidin-1-ylmethyl)benzoxazole

A reaction mixture of 3.00 g (14.1 mmol) of2-chloromethyl-6-nitrobenzoxazole (VIII.1.a), 1.50 mL (18.0 mmol) ofpyrrolidine, and 3.90 g (28.2 mmol) of potassium carbonate in 30 mL ofDMF is stirred for 12 hours at 50° C. After this time, the mixture isdiluted with water and covered with diethyl ether. The precipitateformed is filtered off and dried at 80° C. Yield: 1.80 g (52% oftheory); C₁₂H₁₃N₃O₃; EII mass spectrum: m/z=248 [M+H]⁺.

VIII.1.c: 2-(pyrrolidin-1-ylmethyl)benzoxazol-6-ylamine

Prepared analogously to Example VI.1.d from 1.80 g (7.28 mmol) of6-nitro-2-(pyrrolidin-1-ylmethyl)benzoxazole (VIII.1.b) in methanol assolvent. Yield: 1.10 g (70% of theory); R_(f) value: 0.60 (aluminumoxide, dichloromethane/ethanol=20:1); C₁₂H₁₅N₃O; EII mass spectrum:m/z=218 [M+H]⁺.

EXAMPLE IX. 1 2-(4-dimethylaminomethylphenyl)ethylamine

IX.1.a: (4-dimethylaminomethylphenyl)acetonitrile

A reaction mixture of 4.40 g (20.9 mmol) of (4-bromomethyl)acetonitrile(for preparation method see Magnet. Reson. Chem. 2000, 38, 129-134),1.71 g (21.0 mmol) of dimethylamine hydrochloride, and 9.12 g (66.0mmol) of potassium carbonate in 30 mL of acetone is stirred for 4 hoursat ambient temperature. After this time, the mixture is concentrated byevaporation, taken up in methylene chloride, and washed with water. Theorganic phase is dried over sodium sulfate and then the solvent iseliminated. Yield: 3.60 g (99% of theory); C₁₁H₁₄N₂; EII mass spectrum:m/z=175 [M+H]⁺.

IX.1.b: 2-(4-dimethylaminomethylphenyl)ethylamine

3.60 g (20.7 mmol) of (4-dimethylaminomethylphenyl)acetonitrile (IX.1.a)is dissolved in 50 mL of methanolic ammonia and hydrogenated for 5 hoursat 50° C. at a pressure of 3 bar with hydrogen and 0.45 g of Raneynickel as catalyst. Then the catalyst is filtered off and the solvent iseliminated. Yield: 3.60 g (98% of theory); R_(f) value: 0.20 (silicagel, methylene chloride/methanol=9:1); C₁₁H₁₈N₂; EII mass spectrum:m/z=179 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (IX.2) 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethylamine;-   (IX.3) 2-[4-(3-azaspiro[5.5]undec-3-ylmethyl)phenyl]ethylamine;-   (IX.4)    2-[4-(4-hydroxy-4-phenylpiperidin-1-ylmethyl)phenyl]ethylamine;-   (IX.5) {1-[4-(2-aminoethyl)benzyl]piperidin-4-yl} pyridin-2-ylamine;    and-   (IX.6) 2-methyl-2-[4-(pyrrolidin-1-ylmethyl)phenyl]propylamine.

EXAMPLE X

The following compounds are synthesized using methods already describedin international Patent Application WO 01/27081 or may at least beprepared analogously to methods described therein:

-   (X.1) 4-(piperidin-1-ylmethyl)phenylamine;-   (X.2) 4-(diethylaminomethyl)phenylamine;-   (X.3) 4-(2-diethylaminoethyl)phenylamine;-   (X.4) 3-chloro-4-(piperidin-1-ylmethyl)phenylamine;-   (X.5)    3-chloro-4-[(cis-3,5-dimethylpiperidin-1-yl)methyl]phenylamine;-   (X.6) 4-[(3,5-dimethylpiperidin-1-yl)methyl]phenylamine;-   (X.7) 4-[(4-methoxypiperidin-1-yl)methyl]phenylamine;-   (X.8) 4-[(4-methylpiperidin-1-yl)methyl]phenylamine;-   (X.9) 4-[(4-methylpiperazin-1-yl)methyl]phenylamine;-   (X.10) 4-[(N-methylcyclopropylmethylamino)methyl]phenylamine;-   (X.11) 4-[(2,6-dimethylpiperidin-1-yl)methyl]phenylamine;-   (X.12) 4-(pyrrolidin-1-ylmethyl)phenylamine;-   (X.13) 4-(morpholin-4-ylmethyl)phenylamine; and-   (X.14) 4-[(4-hydroxypiperidin-4-yl)methyl]phenylamine.

EXAMPLE XI.1 N-methyl-4-(2-diethylaminoethoxy)phenylamine

XI.1.a: N-methoxycarbonyl-4-(2-diethylaminoethoxy)phenylamine

76.4 g (0.367 mol) of 4-(2-diethylaminoethoxy)phenylamine (compoundIV.2) and 102 mL (0.733 mol) of triethylamine are dissolved in 400 mL ofTHF and 49.2 g (0.367 mol) of dimethylpyrocarbonate in 200 mL of THF isadded over 45 minutes at ambient temperature. The mixture is stirred fora further 2 hours at ambient temperature. After this time, the solventis evaporated down, the residue is taken up in ethyl acetate and waterand the organic phase is washed twice with water. The solvent iseliminated and the residue purified through an aluminum oxide columnwith petroleum ether/ethyl acetate (3:1) as eluant. Yield: 63.3 g (65%of theory); R_(f) value: 0.60 (aluminum oxide, petroleum ether/ethylacetate=1:3); C₁₄H₂₂N₂O₃; EII mass spectrum: m/z=267 [M+H]⁺.

XI.1.b: N-methyl-4-(2-diethylaminoethoxy)phenylamine

10.7 g (280 mmol) of lithium aluminum hydride is placed in 600 mL of THFand 30.0 g (113 mmol) ofN-methoxycarbonyl-4-(2-diethylaminoethoxy)phenylamine (compound XI.1.a)in 300 mL of THF is carefully added dropwise at 0° C. The mixture isstirred for 12 hours at ambient temperature. After this time, a further7.00 g (183 mmol) of lithium aluminum hydride is added and the mixtureis stirred for a further 24 hours at ambient temperature. After thistime, it is carefully neutralized with sodium hydroxide solution. Themixture is filtered, the filtrate is dried over sodium sulfate, andfinally the solvent is eliminated. Yield: 24.7 g (99% of theory); R_(f)value: 0.45 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1);C₁₃H₂₂N₂O; EII mass spectrum: m/z=223 [M+H]⁺.

The following compound is also synthesized analogously to thepreparation method described above: (XI.2)N-methyl-4-(piperidin-1-ylmethyl)phenylamine.

EXAMPLE XII.1 3-biphenyl-4-ylpropynoicacid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide

0.48 g (2.0 mmol) of biphenyl-4-ylpropynoic acid chloride (forpreparation method see Bioorg. Med. Chem. 1996, 4, 851) is dissolved in15 mL of toluene and 0.58 g (2.4 mmol) of[2-(2-chloro-4-aminophenoxy)ethyl]diethylamine (educt IV.1) in 10 mL oftoluene at ambient temperature is added dropwise. The mixture is stirredfor 8 hours at ambient temperature, the solvent is eliminated, and theresidue is taken up in ethyl acetate and washed with water. The organicphase is dried over sodium sulfate, the solvent is eliminated and theresidue is purified through a silica gel column withdichloromethane/methanol/ammonia (9:1:0.01) as eluant. Yield: 0.28 g(31% of theory); m.p.: 105-108° C.; R_(f) value: 0.50 (silica gel,dichloromethane/methanol/ammonia=9:1:0.1); C₂₇H₂₇ClN₂O₂; EII massspectrum: m/z=447/449 [M+H]⁺.

The following compounds are also synthesized analogously to the methoddescribed above:

-   (XII.2) 3-(2-chloro-4-trifluoromethylphenyl)propynoic    acid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide; and-   (XII.3) 3-(3-bromobiphenyl-4-yl)propynoic    acid-{3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenyl} amide.    Preparation of the Final Compounds

EXAMPLE 1.03-biphenyl-4-yl-N-{3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}-3-oxopropionamide

300 mg (1.00 mmol) of ethyl 3-biphenyl-4-yl-3-oxopropynoate (educt I.1)and 269 mg (1.00 mmol) of3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylamine (educt III.1)are dissolved in 5 mL of toluene and stirred for 8 hours at 120° C. inthe open test tube, while ethanol is distilled off. After cooling,petroleum ether is added, and the precipitate formed is suction filteredand dried in vacuo at 80° C. Yield: 300 mg (61% of theory); R_(f) value:0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); m.p.135-139° C.; C₂₉H₃₁ClN₂O₃; EII mass spectrum: m/z=491/493 [M+H]⁺.

The following compounds of general formula I-1 are prepared analogouslyto Example 1.0, the educts used being shown in the column headed“Educts”: (I-1)

mass m.p. R_(f)- Ex. # R¹R²NX L¹ L² B Educts spectrum [° C.] value* 1.1

—Cl —H

II.1 IV.1 499/501/ 503 [M + H]⁺ 175-180 0.50 (A) 1.2

—H —H

I.1 IV.2 431 [M + H]⁺ 140-142 0.40 (A) 1.3

—OCH₃ —H

I.1 IV.3 461 [M + H]⁺ 108-110 0.60 (B) 1.4

—Cl —Cl

II.2 IV.1 499/501/ 503 [M + H]⁺ 108-111 0.40 (C) 1.5

—H —Cl

II.2 IV.2 465/467 [M + H]⁺ 108-112 0.40 (A) 1.6

—OCH₃ —Cl

II.2 IV.3 495/497 [M + H]⁺ 157-160 0.70 (B) 1.7

—CF₃ —H

I.1 IV.4 497 [M + H]⁺ 130-135 0.45 (D) 1.8

—H —H

I.1 IV.5 445 [M + H]⁺ 152-157 0.45 (D) 1.9

—COO—CH₃ —H

I.1 V.1 487 [M + H]⁺ 131-135 0.45 (D) 1.10

—Cl —H

I.1 VI.1 449/451 [M + H]⁺ 118-122 0.20 (A) 1.11

—Cl —Cl

II.2 VI.1 483/485/ 487 [M + H]⁺ 132-136 0.20 (A) 1.12

—H —H

I.1 X.1 413 [M + H]⁺ 157-160 0.50 (A) 1.13

—H —H

I.1 X.2 401 [M + H]⁺ 126-130 0.60 (A) 1.14

—H —Cl

II.2 X.1 447/449 [M + H]⁺ 72-75 0.50 (A) 1.15

—H —Cl

II.2 X.2 435/437 [M + H]⁺ 155-160 0.50 (A) 1.16

—H —H

II.1 X.1 447/449 [M + H]⁺ 202-204 0.40 (A) 1.17

—H —H

1.1 X.3 415 [M + H]⁺ 144-148 0.50 (D) 1.18

—OCH₃ —H

I.1 III.2 501 [M + H]⁺ 224-228 0.60 (D) 1.19

—OCH₃ —H

I.1 III.3 487 [M + H]⁺ 106-110 0.60 (D) 1.20

—Cl —H

II.1 X.4 482 [M + H]⁺ 175-177 0.45 (C) 1.21

—Cl —H

II.1 X.5 509/511/ 513 [M + H]⁺ 174-177 0.80 (C) 1.22

—H —H

II.1 X.6 475/477 [M + H]⁺ 175-178 0.45 (D) 1.23

—H —H

II.1 X.7 477/479 [M + H]⁺ 178-181 0.50 (C) 1.24

—H —H

II.1 X.8 461/463 [M + H]⁺ 168-170 0.35 (C) 1.25

—H —H

II.1 X.9 462/464 [M + H]⁺ 176-178 0.30 (D) 1.26

—H —H

II.1 X.10 447/449 [M + H]⁺ 167-170 0.50 (C) 1.27

—H —H

II.1 X.11 475/477 [M + H]⁺ 168-171 0.45 (C) 1.28

—H —H

II.1 X.12 433/435 [M + H]⁺ 187-189 0.35 (C) 1.29

—H —H

II.1 X.2 435/437 [M + H]⁺ 175-178 0.35 (C) 1.30

—H —H

II.1 X.13 449/451 [M + H]⁺ 188-190 0.45 (C) 1.31

—H —H

II.1 X.14 463/465 [M + H]⁺ 146-149 0.30 (C) 1.32

—Cl —H

I.1 III.4 479/481 [M + H]⁺ 120-126 0.70 (D) 1.33

—Cl —H

I.1 III.5 477/479 [M + H]⁺ 130-132 0.40 (C) 1.34

—Cl —H

I.1 III.6 507/509 [M + H]⁺ 120-125 0.40 (C) 1.35

—Cl —H

I.1 III.7 492/494 [M + H]⁺ 130-135 0.30 (C) 1.36

—Cl —H

I.1 III.8 493/495 [M + H]⁺ 115-118 0.30 (C) 1.37

—Cl —H

I.1 VI.2 475/477 [M + H]⁺ 227-232 0.44 (C) 1.38

—Cl —H

I.1 VI.3 491/493 [M + H]⁺ >130 0.53 (C) 1.39

—Cl —H

I.1 VI.4 449/451 [M + H]⁺ 81-85 0.32 (C) 1.40

—Cl —H

I.1 VI.5 546/548 [M + H]⁺ 171-175 0.24 (C) 1.41

—Cl —H

I.1 VI.6 545/547 [M + H]⁺ 187-191 0.38 (C) 1.42

—Cl —H

I.1 VI.7 576/578 [M + H]⁺ 157-159 0.42 (C) 1.43

—Cl —H

I.1 VI.8

EXAMPLE 2

The following compounds of general formula II-1 are prepared analogouslyto Example 1.0, the educts used being shown in the column headed“Educts”: (II-1)

Ex. # R¹R²NX L¹ L² L³ Educts mass spectrum m.p. [° C.] R_(f)-value* 2.0

—Cl —H —OCH₃ II.3 IV.1 419/421 [M + H]⁺ 120-122 0.40 (A)

EXAMPLE 3

The following compounds of general formula III-1 are preparedanalogously to Example 1.0, the educts used being shown in the columnheaded “Educts”: (III-1)

Ex. # R¹R²NX L² B Educts mass spectrum m.p. [° C.] R_(f)-value* 3.0

—Cl

II.2 VII.1 419/421 [M + H]⁺ 120-122 0.40 (A) 3.1

—H

I.1 VII.1 452 [M + H]⁺ 135-142 0.50 (A) 3.2

—H

I.1 VII.2 466 [M + H]⁺ 60-65 0.50 (D) 3.3

—H

I.1 VII.3 480 [M + H]⁺ 127-129 0.50 (D) 3.4

—H

I.1 VII.4 482 [M + H]⁺ 139-144 0.65 (D) 3.5

—H

I.1 VII.5 514 [M + H]⁺ 83-86 0.60 (D) 3.6

—H

I.1 VII.6 516 [M + H]⁺ 85-90 0.70 (D) 3.7

—H

I.1 VII.7 454 [M + H]⁺ 99-104 0.55 (D)

EXAMPLE 4

The following compound of general formula IV-1 is prepared analogouslyto Example 1.0, the educts used being shown in the column headed“Educts”: (IV-1)

Ex. # R¹R²NX L² B Educts mass spectrum m.p. [° C.] R_(f)-value* 4.0

—H

I.1 VIII.1 440 [M + H]⁺ 135-138 0.55 (D)

EXAMPLE 5

The following compounds of general formula V-1 are prepared analogouslyto Example 1.0, the educts used being shown in the column headed“Educts”: (V-1)

Ex. # R¹R²NX R^(7a)/R^(7b) B Educts mass spectrum m.p. [° C.]R_(f)-value* 5.0

—H

I.1 IX.1 401 [M + H]⁺ 120-125 0.40 (D) 5.1

—H

I.1 IX.2 427 [M + H]⁺ 121-125 0.55 (D) 5.2

—H

I.1 IX.3 509 [M + H]⁺ 107-111 0.40 (D) 5.3

—H

I.1 IX.4 533 [M + H]⁺ 98-103 0.40 (D) 5.4

—H

I.1 IX.5 533 [M + H]⁺ 109-112 0.30 (D) 5.5

—CH₃

I.1 IX.6 455 [M + H]⁺ 100-106 0.40 (D)

EXAMPLE 6

The following compounds of general formula VI-1 are prepared analogouslyto Example 1.0, the educts used being shown in the column headed“Educts”: (VI-1)

Ex. # R¹R²NX L¹ L² B Educts mass spectrum m.p. [° C.] R_(f)-value* 6.0

—H —H

I.1 XI.1 445 [M + H]⁺ 108-112 0.50 (D) 6.1

—H —H

I.1 XI.1 427 [M + H]⁺ 175 0.70 (A)

EXAMPLE 7.03-biphenyl-4-yl-N-[3-chloro-4-(2-diethylaminoethoxy)phenyl]-3-oxopropionamide

0.16 g (0.36 mmol) of 3-biphenyl-4-ylpropynoicacid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide (educt XII.1) isdissolved in 10 mL of aqueous ethanol and 0.10 mL (1.0 mmol) ofpiperidine is added. The mixture is stirred for 8 hours at refluxtemperature. After cooling, the solvent is eliminated, and the residueis suspended in ether and filtered off. The residue is dried in vacuo at50° C. Yield: 75 mg (45% of theory); R_(f) value: 0.40 (silica gel,methylene chloride/methanol/ammonia=9:1:0.01); m.p. 148° C.-151° C.;C₂₇H₂₉ClN₂O₃; EII mass spectrum: m/z=465/467 [M+H]⁺.

The following compounds of general formula VII-1 are preparedanalogously to Example 7.0, the educts used being shown in the columnheaded “Educts”: (VII-1)

Ex. # R¹R²NX L¹ L² L³ Educts mass spectrum m.p. [° C.] R_(f)-value* 7.1

—Cl —Cl —CF₃ XII.2 491/493/495 [M + H]⁺ n.b. 0.40 (E) 7.2

—Cl —Br

XII.3 553/555/557 [M + H]⁺ 139-144 0.48 (C)

EXAMPLE 8.05-(3-biphenyl-4-yl-3-oxopropionylamino)-2-(2-pyrrolidin-1-ylethoxy)benzoicacid

0.25 g (0.51 mmol) of methyl5-(3-biphenyl-4-yl-3-oxopropionylamino)-2-(2-pyrrolidin-1-ylethoxy)benzoate(compound 1.9) is dissolved in 20 mL of methanol, 2.0 mL of 1N sodiumhydroxide solution is added, and the mixture is stirred for 3 hours at50° C. and 12 hours at ambient temperature. After this time, another 1.0mL of 1N sodium hydroxide solution is added and the mixture is stirredfor another 3 hours at 50° C. After cooling, 3.0 mL of 1N hydrochloricacid is added and the mixture is stirred for 1 hour at ambienttemperature. The solvent is evaporated down, and the residue is taken upin a little methanol and the precipitate obtained is suction filteredand dried in vacuo at 80° C. Yield: 240 mg (100% of theory); R_(f)value: 0.20 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1);m.p. 236° C.-240° C.; C₂₈H₂₈N₂O₅; EII mass spectrum: m/z=473 [M+H]⁺.

EXAMPLE 9.0N-{4-[2-(4-aminopiperidin-1-yl)ethyl]-3-chlorophenyl}-3-biphenyl-4-yl-3-oxopropionamide

0.19 g (0.33 mmol) ofN-{4-[2-(4-tert-butoxycarbonylaminopiperidin-1-yl)ethyl]-3-chlorophenyl}-3-biphenyl-4-yl-3-oxopropionamide(compound 1.41) is dissolved in 7 mL of methylene chloride, 500 mL oftrifluoroacetic acid is added, and the mixture is stirred for 12 hoursat ambient temperature. After this time, saturated sodium hydrogencarbonate solution is added and the precipitate formed is suctionfiltered. The residue is dried in vacuo over sodium hydroxide. Yield:160 mg (100% of theory); R_(f) value: 0.10 (silica gel, methylenechloride/methanol=9:1); m.p. above 144° C. (decomposition);C₂₈H₃₀ClN₃O₂; EII mass spectrum: m/z=476/478 [M+H]⁺.

EXAMPLE 10

The following compounds of general formula VIII-1 are preparedanalogously to Example 1.0, the educts used being shown in the columnheaded “Educts”: (VIII-1)

Ex. # R¹R²NX L¹ L² L³ Educts mass spectrum m.p. [° C.] R_(f)-value* 10.0

—H —H

I.1 VI.9 414 [M + H]⁺ 178-182 0.40 (A)

The following compounds are prepared analogously to the foregoingExamples:

Example R¹R²NX L¹ L² B 11

—Cl —H

12

—Cl —H

13

—Cl —H

14

—Cl —H

15

—Cl —H

16

—Cl —H

17

—Cl —H

18

—Cl —H

19

—Cl —H

20

—Cl —H

21

—Cl —H

22

—Cl —H

23

—Cl —H

24

—Cl —H

25

—Cl —H

26

—Cl —H

27

—Cl —H

28

—Cl —H

29

—Cl —H

30

—Cl —H

31

—Cl —H

32

—Cl —H

33

—Cl —H

34

—Cl —H

35

—Cl —H

36

—Cl —H

37

—Cl —H

38

—Cl —H

39

—Cl —H

40

—Cl —H

41

—Cl —H

42

—Cl —H

43

—Cl —H

44

—Cl —H

45

—Cl —H

46

—Cl —H

47

—Cl —Cl —CF₃ 48

—Cl —Cl —CF₃ 49

—Cl —Cl —CF₃ 50

—Cl —Cl —CF₃ 51

—Cl —Cl —CF₃ 52

—Cl —Cl —CF₃ 53

—Cl —Cl —CF₃ 54

—Cl —Cl —CF₃ 55

—Cl —Cl —CF₃ 56

—Cl —Cl —CF₃ 57

—Cl —Cl —CF₃ 58

—Cl —Cl —CF₃ 59

—Cl —Cl —CF₃ 60

—Cl —Cl —CF₃ 61

—Cl —Cl —CF₃ 62

—Cl —Cl —CF₃ 63

—Cl —Cl —CF₃ 64

—Cl —Cl —CF₃ 65

—Cl —Cl —CF₃ 66

—Cl —Cl —CF₃ 67

—Cl —Cl —CF₃ 68

—Cl —Cl —CF₃ 69

—Cl —Cl —CF₃ 70

—Cl —Cl —CF₃ 71

—Cl —Cl —CF₃ 72

—Cl —H

73

—Cl —H

74

—Cl —H

75

—Cl —H

76

—Cl —H

77

—Cl —H

Some test methods for determining an MCH-receptor antagonistic activitywill now be described. In addition, other test methods known to theskilled man may be used, e.g., by inhibiting the MCH-receptor-mediatedinhibition of cAMP production, as described by M. Hoogduijn, et al.,Melanin-Concentrating Hormone and its Receptor are Expressed andFunctional in Human Skin, Biochem. Biophys. Res Commun. 296 (2002) pp.698-701, and by biosensory measurement of the binding of MCH to the MCHreceptor in the presence of antagonistic substances by plasmonresonance, as described by O.P Karlsson and S. Lofas, Flow-MediatedOn-Surface Reconstitution of G-Protein Coupled Receptors forApplications in Surface Plasmon Resonance Biosensors, Anal. Biochem. 300(2002), 132-138. Other methods of testing antagonistic activity to MCHreceptors are contained in the references and patent documents mentionedhereinbefore, and the description of the test methods used is herebyincorporated in this application. MCH-1 Receptor Binding Test Method:MCH binding to hMCH-1R transfected cells Species: Human Test cell:hMCH-1R stably transfected into CHO/Galpha16 cells Results: IC₅₀ values

Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1Rare resuspended using a syringe (needle 0.6×25 mm) and diluted in testbuffer (50 mM HEPES, 10 mM MgCl₂, 2 mM EGTA, pH 7.00; 0.1% bovine serumalbumin (protease-free), 0.021% bacitracin, 1 μg/mL aprotinin, 1 μg/mLleupeptin, and 1 μM phosphoramidone) to a concentration of 5 to 15μg/mL.

200 microliters of this membrane fraction (contains 1 to 3 μg ofprotein) are incubated for 60 minutes at ambient temperature with 100 pMof ¹²⁵I-tyrosyl melanin concentrating hormone (¹²⁵I-MCH commerciallyobtainable from NEN) and increasing concentrations of the test compoundin a final volume of 250 microliters. After the incubation the reactionis filtered using a cell harvester through 0.5% PEI treated fiberglassfilters (GF/B, Unifilter Packard). The membrane-bound radioactivityretained on the filter is then determined after the addition ofscintillator substance (Packard Microscint 20) in a measuring device(TopCount of Packard).

The non-specific binding is defined as bound radioactivity in thepresence of 1 micromolar MCH during the incubation period. The analysisof the concentration binding curve is carried out on the assumption ofone receptor binding site.

Standard:

Non-labelled MCH competes with labelled ¹²⁵I-MCH for the receptorbinding with an IC₅₀ value of between 0.06 and 0.15 nM. The KD value ofthe radioligand is 0.156 nM. MCH-1 Receptor-Coupled Ca²⁺ MobilizationTest Method: Calcium mobilization test with human MCH (FLIPR³⁸⁴)Species: Human Test cells: CHO/Galpha 16 cells stably transfected withhMCH-R1 Results: 1st measurement: % stimulation of the reference (MCH10⁻⁶ M) 2nd measurement: pKB value Reagents: HBSS (10×) (GIBCO) HEPESbuffer (1 M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (MolecularProbes) Probenecid (Sigma) MCH (Bachem) bovine serum albumin(protease-free) (Serva) DMSO (Serva) Ham's F12 (BioWhittaker) FCS(BioWhittaker) L-Glutamine (GIBCO) Hygromycin B (GIBCO) PENStrep(BioWhittaker) Zeocin (Invitrogen)

Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cellculture medium (with L-glutamine; BioWhittaker; Cat. No.: BE12-615F).This contains per 500 mL 10% FCS, 1% PENStrep, 5 mL L-glutamine (200 mMstock solution), 3 mL hygromycin B (50 mg/ml in PBS), and 1.25 mL zeocin(100 μg/ml stock solution). One day before the experiment, the cells areplated on a 384-well microtiter plate (black-walled with a transparentbase, made by Costar) in a density of 2500 cells per cavity andcultivated in the above medium overnight at 37° C., 5% CO₂, and 95%relative humidity. On the day of the experiment the cells are incubatedwith cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid havebeen added, at 37° C. for 45 minutes. After charging with fluorescentdye the cells are washed four times with Hanks buffer solution (1×HBSS,20 mM HEPES), which has been combined with 0.07% Probenicid. The testsubstances are diluted in Hanks buffer solution, combined with 2.5%DMSO. The background fluorescence of non-stimulated cells is measured inthe presence of substance in the 384-well microtiter plate five minutesafter the last washing step in the FLIPR³⁸⁴ apparatus (MolecularDevices; excitation wavelength: 488 nm; emission wavelength: bandpass510 to 570 nm). To stimulate the cells, MCH is diluted in Hanks bufferwith 0.1% BSA, pipetted into the 384-well cell culture plate 35 minutesafter the last washing step and the MCH-stimulated fluorescence is thenmeasured in the FLIPR³⁸⁴ apparatus.

Data Analysis:

1st measurement: The cellular Ca²⁺ mobilization is measured as the peakof the relative fluorescence minus the background and is expressed asthe percentage of the maximum signal of the reference (MCH 10⁻⁶M). Thismeasurement serves to identify any possible agonistic effect of a testsubstance.

2nd measurement: The cellular Ca²⁺ mobilization is measured as the peakof the relative fluorescence minus the background and is expressed asthe percentage of the maximum signal of the reference (MCH 10⁻⁶M, signalis standardized to 100%). The EC50 values of the MCH dosage activitycurve with and without test substance (defined concentration) aredetermined graphically by the GraphPad Prism 2.01 curve program. MCHantagonists cause the MCH stimulation curve to shift to the right in thegraph plotted.

The inhibition is expressed as a pKB value:pKB=log(EC _(50(testsubstance+MCH)) /EC _(50(MCH))−1)-log c_((testsubstance))

The compounds according to the invention, including their salts, exhibitan MCH-receptor antagonistic activity in the tests mentioned above.Using the MCH-1 receptor binding test described above an antagonisticactivity is obtained in a dosage range from about 10⁻¹⁰ to 10⁻⁵ M,particularly from 10⁻⁹ to 10⁻⁶ M.

The following IC₅₀ values were determined using the MCH-1 receptorbinding test described above: Compound according to Example No.Structure IC₅₀ value 5.1

63.7 nM 7.1

34.8 nM

Some examples of formulations will be described hereinafter, wherein theterm “active substance” denotes one or more compounds according to theinvention, including their salts. In the case of one of the combinationswith one or more active substances described, the term “activesubstance” also includes the additional active substances.

EXAMPLE A Capsules for Powder Inhalation Containing 1 mg ActiveSubstance

Composition:

1 capsule for powder inhalation contains: active substance 1.0 mglactose 20.0 mg hard gelatin capsules 50.0 mg 71.0 mgMethod of Preparation:

The active substance is ground to the particle size required forinhalation. The ground active substance is homogeneously mixed with thelactose. The mixture is packed into hard gelatin capsules.

EXAMPLE B Inhalable Solution for RESPIMAT® Containing 1 mz ActiveSubstance

Composition:

1 spray contains: active substance 1.0 mg benzalkonium chloride 0.002 mgdisodium edetate 0.0075 mg purified water to 15.0 μLMethod of Preparation:

The active substance and benzalkonium chloride are dissolved in waterand packed into RESPIMAT® cartridges.

EXAMPLE C Inhalable Solution for Nebulizer Containing 1 mg ActiveSubstance

Composition:

1 vial contains: active substance 0.1 g sodium chloride 0.18 gbenzalkonium chloride 0.002 g purified water to 20.0 mLMethod of Preparation:

The active substance, sodium chloride, and benzalkonium chloride aredissolved in water.

EXAMPLE D Propellant Type Metered Dose Aerosol Containing 1 mg ActiveSubstance

Composition:

1 spray contains: active substance 1.0 mg lecithin 0.1% propellant gasto 50.0 μLMethod of Preparation:

The micronized active substance is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

EXAMPLE E Nasal Spray Containing 1 mg Active Substance

Composition: active substance 1.0 mg sodium chloride 0.9 mg benzalkoniumchloride 0.025 mg disodium edetate 0.05 mg purified water to 0.1 mLMethod of Preparation:

The active substance and the excipients are dissolved in water andtransferred into a corresponding container.

EXAMPLE F Injectable Solution Containing 5 mg of Active Substance Per 5mL

Composition: active substance 5 mg glucose 250 mg human serum albumin 10mg glycofurol 250 mg water for injections to 5 mLMethod of Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI) andhuman serum albumin is added. The active ingredient is dissolved withheating, made up to specified volume with WfI, and transferred intoampoules under nitrogen gas.

EXAMPLE G Injectable Solution Containing 100 mg of Active Substance Per20 mL

Composition: active substance 100 mg monopotassium dihydrogen phosphate(KH₂PO₄) 12 mg disodium hydrogen phosphate (Na₂HPO₄.2H₂O) 2 mg sodiumchloride 180 mg human serum albumin 50 mg Polysorbate 80 20 mg water forinjections to 20 mLMethod of Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate, anddisodium hydrogen phosphate are dissolved in water for injections (WfI)and human serum albumin is added. The active ingredient is dissolvedwith heating, made up to specified volume with WfI, and transferred intoampoules.

EXAMPLE H Lyophilisate Containing 10 mg of Active Substance

Composition: Active substance 10 mg Mannitol 300 mg human serum albumin20 mgMethod of Preparation:

Mannitol is dissolved in water for injections (WfI) and human serumalbumin is added. The active ingredient is dissolved with heating, madeup to specified volume with WfI, transferred into vials, andfreeze-dried.

Solvent for Lyophilisate: Polysorbate 80 = Tween 80 20 mg mannitol 200mg water for injections to 10 mLMethod of Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI)and transferred into ampoules.

EXAMPLE I Tablets Containing 20 mg of Active Substance

Composition: active substance 20 mg lactose 120 mg maize starch 40 mgmagnesium stearate 2 mg Povidone K 25 18 mgMethod of Preparation:

Active substance, lactose, and maize starch are homogeneously mixed,granulated with an aqueous solution of Povidone, mixed with magnesiumstearate, and compressed in a tablet press (weight of tablet: 200 mg).

EXAMPLE J Capsules Containing 20 mg Active Substance

Composition: active substance 20 mg maize starch 80 mg highly dispersedsilica 5 mg magnesium stearate 2.5 mgMethod of Preparation:

Active substance, maize starch, and silica are homogeneously mixed,mixed with magnesium stearate, and the mixture is packed into size 3hard gelatin capsules in a capsule filling machine.

EXAMPLE K Suppositories Containing 50 mg of Active Substance

Composition: active substance 50 mg hard fat (Adeps solidus) q.s. to1700 mgMethod of Preparation:

Hard fat is melted at about 38° C. and ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

EXAMPLE L Injectable Solution Containing 10 mg of Active Substance Per 1mL

Composition: active substance 10 mg mannitol 50 mg human serum albumin10 mg water for injections to 1 mLMethod of Preparation:

Mannitol is dissolved in water for injections (WfI) and human serumalbumin is added. The active ingredient is dissolved with heating, madeup to specified volume with WfI, and transferred into ampoules undernitrogen gas.

1. A compound of formula I

wherein: R¹ and R² are each independently H, a C₁₋₈-alkyl, orC₃₋₇-cycloalkyl group optionally mono- or polysubstituted by the groupR¹¹, wherein a —CH₂— group in position 3 or 4 of a 5-, 6-, or 7-memberedcycloalkyl group is optionally replaced by —O—, —S—, or —NR¹³—, or aphenyl or pyridinyl group optionally mono- or polysubstituted by thegroup R²⁰ and/or monosubstituted by nitro, or R¹ and R² form aC₂₋₈-alkylene bridge, wherein one or two —CH₂— groups are optionallyindependently replaced by —CH═N— or —CH═CH—, and/or one or two —CH₂—groups are optionally independently replaced by —O—, —S—, —SO—, —(SO₂)—,—C(═CH₂)—, or —NR¹³— in such a way that heteroatoms are not directlyjoined together, and that a group —CO— is not directly linked to thegroup R¹R²N—, wherein in the alkylene bridge one or more H atoms areoptionally replaced by R¹⁴, and the alkylene bridge is optionallyindependently substituted by one or two Cy groups such that the bondbetween the alkylene bridge and the Cy group is made via a single ordouble bond, via a common C atom forming a spirocyclic ring system, viatwo common adjacent C and/or N atoms forming a fused bicyclic ringsystem, or via three or more C and/or N atoms forming a bridged ringsystem; R³ is H, C₁₋₆-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, or phenyl-C₁₋₃-alkyl; X is a C₁₋₈-alkylenebridge, wherein a —CH₂— group which is not directly linked to the groupR¹R²N— is optionally replaced by —CH═CH— or —C≡C—, and/or one or twonon-adjacent —CH₂— groups, which are not directly linked to the groupR¹R²N—, are optionally independently replaced by —O—, —S—, —(SO)—,—(SO₂)—, —CO—, or —NR⁴— in such a way that in each case two O, S, or Natoms or an O and an S atom are not directly joined together, whereinthe bridge X is optionally connected to R¹ including the N atom linkedto R¹ and X, forming a heterocyclic group, wherein the bridge X isoptionally additionally connected to R² including the N atom connectedto R²and X, forming a heterocyclic group, and wherein two C atoms or a Cand an N atom of the bridge X are optionally joined together by anadditional C₁₋₄-alkylene bridge, and a C atom not directly connected toa heteroatom is optionally substituted by R¹⁰ and/or one or two C atomsare optionally independently substituted by one or two identical ordifferent substituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,C₄₋₇-cycloalkenyl, and C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, wherein two alkyland/or alkenyl substituents are optionally joined together, forming acarbocyclic ring system; Z is a single bond or—CR^(7a)R^(7b)—CR^(7c)R^(7d)—; Y has one of the meanings given for Cy;while R¹ may be connected to Y including the group X and the N atomconnected to R¹ and X, forming a heterocyclic group fused to Y, and/or Xmay be connected to Y forming a carbo- or heterocyclic group fused to Y,and A has one of the meanings given for Cy, B has one of the meaningsgiven for Cy, b has the value 0 or 1, Cy is a saturated 3- to 7-memberedcarbocyclic group, an unsaturated 4- to 7-membered carbocyclic group, aphenyl group, a saturated 4- to 7-membered or unsaturated 5- to7-membered heterocyclic group with an N, O, or S atom as heteroatom, asaturated or unsaturated 5- to 7-membered heterocyclic group with two ormore N atoms or with one or two N atoms and one O or S atom asheteroatoms, an aromatic heterocyclic 5- or 6-membered group with one ormore identical or different heteroatoms selected from N, O, and/or S,wherein the 4-, 5-, 6-, or 7-membered groups of Cy are optionally fusedto a phenyl or pyridine ring via two common adjacent C atoms, and in the5-, 6-, or 7-membered groups of Cy one or two non-adjacent —CH₂ groupsare optionally independently replaced by a —CO—, —C(═CH₂)—, —(SO)—, or—(SO₂)— group, and the saturated 6- or 7-membered groups of Cy areoptionally bridged ring systems with an imino, N—(C₁₋₄-alkyl)-imino,methylene, C₁₋₄-alkyl-methylene, or di-(C₁₋₄-alkyl)-methylene bridge,and the cyclic groups of Cy are optionally mono- or polysubstituted byR²⁰ at one or more C atoms, and in the case of a phenyl group areoptionally additionally monosubstituted by nitro, and/or one or more NHgroups is optionally substituted by R²¹, R⁴ has one of the meaningsgiven for R¹⁷ or denotes C₃₋₆-alkenyl, or C₃₋₆-alkynyl; R^(5a) andR^(5b) are each independently H, C₁₋₃-alkyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, CF₃, F, or Cl, wherein if R^(5a) and R^(5b)are each an alkyl, they are optionally joined together such that aC₃₋₇-cycloalkyl group is formed together with the C atom to which R^(5a)and R^(5b) are linked; R^(7a) and R^(7c) are each independently H, F,Cl, C₁₋₄-alkyl, or CF₃; R^(7b) and R^(7d) are each independently H, F,C₁₋₄-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, or CF₃, whereinif R^(7a) and R^(7b) are each alkyl, they are optionally joined togethersuch that a C₃₋₇-cycloalkyl group is formed together with the C atom towhich R^(7a) and R^(7b) are linked, and/or if R^(7c) and R^(7d) are eachalkyl, they are optionally joined together such that a C₃₋₇-cycloalkylgroup is formed together with the C atom to which R^(7c) and R^(7d) arelinked, or R^(7b) and R^(7d) are each alkyl, they are optionally joinedtogether such that a C₃₋₇-cycloalkyl group is formed together with thetwo C atoms to which R^(7b) and R^(7d) are linked; R¹⁰ is hydroxy,hydroxy-C₁₋₃-alkyl, C₁₋₄-alkoxy, (C₁₋₄-alkoxy)-C₁₋₃-alkyl, carboxy,C₁₋₄-alkoxycarbonyl, amino, C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino,cyclo-C₃₋₆-alkyleneimino, amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkyl,amino-C₁₋₃-alkoxy, C₁₋₄-alkyl-amino-C₁₋₃-alkoxy,di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkoxy, cyclo-C₃₋₆-alkyleneimino-C₁₋₃-alkoxy,aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,or cyclo-C₃₋₆-alkyleneimino-carbonyl; R¹¹ is C₁₋₃-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, R¹⁵—O—, R¹⁵—O—C₁₋₃-alkyl-, R¹⁵—O—CO—, R¹⁵—CO—O, cyano,R¹⁶R¹⁷N—, R¹⁸R¹⁹N—CO—, or Cy; R¹³ has one of the meanings given for R¹⁷;R¹⁴ is halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, R¹⁵—O—,R¹⁵—O—CO—, R¹⁵—CO, R¹⁵—CO—O—, R¹⁶R¹⁷N—, R¹⁸R¹⁹N—CO—R¹⁵—O—C₁₋₃-alkyl,R¹⁵—O—CO—C₁₋₃-alkyl, R¹⁵—O—CO—NH—, R¹⁵—SO₂—NH—, R¹⁵—O—CO—NH—C₁₋₃-alkyl,R¹⁵—SO₂—NH—C₁₋₃-alkyl, R¹⁵—CO—C₁₋₃-alkyl, R¹⁵—CO—O—C₁₋₃-alkyl,R¹⁶R¹⁷N—C₁₋₃-alkyl, R¹⁸R¹⁹N—CO—C₁₋₃-alkyl, or Cy—C₁₋₃-alkyl-; R¹⁵ is H,C₁₋₄-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, phenyl,phenyl-C₁₋₃-alkyl, pyridinyl, or pyridinyl-C₁₋₃-alkyl; R¹⁶ is H,C₁₋₆-alkyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,C₄₋₇-cycloalkenyl, C₄₋₇-cycloalkenyl-C₁₋₃-alkyl, hydroxy-C₂₋₃-alkyl,C₁₋₄-alkoxy-C₂₋₃-alkyl, amino-C₂₋₆-alkyl, C₁₋₄-alkyl-amino-C₂₋₆-alkyl,di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl, orcyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl; R¹⁷ has one of the meanings givenfor R¹⁶ or denotes phenyl, phenyl-C₁₋₃-alkyl, pyridinyl, dioxolan-2-yl,C₁₋₄-alkylcarbonyl, hydroxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxycarbonyl,C₁₋₄-alkoxycarbonyl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonylamino-C₂₋₃-alkyl,N—(C₁₋₄-alkylcarbonyl)-N—(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl,C₁₋₄-alkylsulfonyl, C₁₋₄-alkylsulfonylamino-C₂₋₃-alkyl, orN—(C₁₋₄-alkylsulfonyl)-N—(C₁₋₄-alkyl)-amino-C₂₋₃-alkyl-; R¹⁸ and R¹⁹ areeach independently H or C₁₋₆-alkyl; R²⁰ is halogen, hydroxy, cyano,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy-C₁₋₄-alkyl, R²²—C₁₋₃-alkyl, or hasone of the meanings given for R²²; R²¹ is C₁₋₄-alkyl,hydroxy-C₂₋₃-alkyl, C₁₋₄-alkoxy-C₂₋₆-alkyl, C₁₋₄-alkyl-amino-C₂₋₆-alkyl,di-(C₁₋₄-alkyl)-amino-C₂₋₆-alkyl, cyclo-C₃₋₆-alkyleneimino-C₂₋₆-alkyl,phenyl-C₁₋₃-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxy-carbonyl, orC₁₋₄-alkylsulfonyl; R²² is phenyl-C₁₋₃-alkoxy,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkoxy, C₁₋₄-alkoxy, C₁₋₄-alkylthio,carboxy, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,cyclo-C₃₋₆-alkyl-amino-carbonyl, cyclo-C₃₋₆-alkyleneimino-carbonyl,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl-aminocarbonyl,phenyl-amino-carbonyl, C₁₋₄-alkyl-sulfonyl, C₁₋₄-alkyl-sulfinyl,C₁₋₄-alkyl-sulfonylamino, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,C₁₋₄-alkyl-carbonyl-amino, cyclo-C₃₋₆-alkyleneimino,phenyl-C₁₋₃-alkylamino, N—(C₁₋₄-alkyl)-phenyl-C₁₋₃-alkylamino,acetylamino, propionylamino, phenylcarbonylamino,phenylcarbonylmethylamino, hydroxy-C₁₋₃-alkylaminocarbonyl,(4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl,(1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl,(4-methyl-1-piperazinyl)carbonyl, aminocarbonyl-amino, orC₁₋₄-alkylaminocarbonylamino, wherein in each of the abovementionedgroups and radicals one or more C atoms are optionally additionallymono- or polysubstituted by F and/or in each case one or two C atoms areoptionally independently additionally monosubstituted by Cl or Br and/orone or more phenyl rings optionally independently additionally compriseone, two, or three substituents selected from the group F, Cl, Br, I,C₁₋₄-alkyl, C₁₋₄-alkoxy, difluoromethyl, trifluoromethyl, hydroxy,amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino,aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy,amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl, anddi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl and/or are optionally monosubstitutedby nitro, and the H atom of a carboxy group or an H atom bound to an Natom are each optionally replaced by a group which can be cleaved invivo, or a tautomer, enantiomer, salt, or mixture thereof.
 2. Thecompound according to claim 1, wherein R¹ and R² are each independentlyH, C₁₋₆-alkyl, C₃₋₅-alkenyl, C₃₋₅-alkynyl, C₃₋₇-cycloalkyl,hydroxy-C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,(hydroxy-C₃₋₇-cycloalkyl)-C₁₋₃-alkyl, hydroxy-C₂₋₄-alkyl, NC—C₂₋₃-alkyl,C₁₋₄-alkoxy-C₂₋₄-alkyl, hydroxy-C₁₋₄-alkoxy-C₂₋₄-alkyl,C₁₋₄-alkoxy-carbonyl-C₁₋₄-alkyl, carboxyl-C₁₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₄-alkyl-amino-C₂₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl, pyrrolidin-3-yl,N—(C₁₋₄-alkyl)-pyrrolidinyl, pyrrolidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-pyrrolidinyl-C₁₋₃-alkyl, piperidin-3-yl or -4-yl,N—(C₁₋₄-alkyl)-piperidin-3-yl or -4-yl, piperidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-piperidinyl-C₁₋₃-alkyl, tetrahydropyran-3-yl,tetrahydropyran-4-yl, tetrahydropyranyl-C₁₋₃-alkyl,tetrahydrofuran-3-yl, tetrahydrofuranyl-C₁₋₃-alkyl, phenyl,phenyl-C₁₋₃-alkyl, pyridyl, or pyridyl-C₁₋₃-alkyl, wherein in each groupone or more C atoms are optionally mono- or polysubstituted by F and/orone or two C atoms are optionally independently monosubstituted by Cl orBr, and each phenyl or pyridyl group is optionally mono- orpolysubstituted by R²⁰ and/or monosubstituted by nitro.
 3. The compoundaccording to claim 1, wherein R¹ and R² form an alkylene bridge suchthat R¹R²N— forms azetidine, pyrrolidine, piperidine, azepan,2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine,2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine,piperazine, wherein the free imine function is substituted by R¹³,piperidin-4-one, morpholine, and thiomorpholine, wherein one or more Hatoms are optionally replaced by R¹⁴, and/or the alkylene bridge isoptionally independently substituted by one or two Cy groups such thatthe bond between the alkylene bridge and the Cy group is made via asingle or double bond, via a common C atom forming a spirocyclic ringsystem, via two common adjacent C and/or N atoms forming a fusedbicyclic ring system, or via three or more C and/or N atoms forming abridged ring system.
 4. The compound according to claim 1, wherein thegroup

thereof is one of the following partial formulae

wherein one or more H atoms of the heterocycle formed by the groupR^(l)R²N— are optionally replaced by R¹⁴ and the ring connected to theheterocycle formed by the group R^(l)R²N— is optionally mono- orpolysubstituted at one or more C atoms by R²⁰, and in the case of aphenyl ring, is optionally additionally monosubstituted by nitro; X′ andX″ are each independently a single bond or C₁₋₃-alkylene and, if Y islinked to X′ or X″ via a C atom, are each also —C₁₋₃-alkylene-O—,—C₁₋₃-alkylene-NH—, or —C₁₋₃-alkylene-N(C₁₋₃-alkyl)-, and X″ isadditionally —O—C₁₋₃-alkylene, —NH—C₁₋₃-alkylene, or—N(C₁₋₃-alkyl)—C₁₋₃-alkylene, and, if Y is linked to X″ via a C atom, isalso —NH—, —N(C₁₋₃-alkyl)-, or —O—, wherein in each of X′ and X″ a Catom is optionally independently substituted by R¹⁰, and/or one or two Catoms are optionally independently substituted by one or twosubstituents selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl andC₄₋₇-cycloalkenyl-C₁₋₃-alkyl, wherein two alkyl and/or alkenylsubstituents is optionally joined together forming a carbocyclic ringsystem, and in each of X′ and X″ one or more C atoms is optionallyindependently mono- or polysubstituted by F and/or one or two C atoms isoptionally independently monosubstituted by Cl or Br.
 5. The compoundaccording to claim 1, wherein X is an unbranched C₁₋₄-alkylene bridgeand, if Y is linked to X via a C atom, is also —CH₂—CH═CH—, —CH₂—C≡C—,C₂₋₄-alkylenoxy, or C₂₋₄-alkylene-NR⁴—, wherein the bridge X isoptionally connected to R¹, including the N atom connected to R¹ and X,forming a heterocyclic group, and the bridge X is optionallyadditionally connected to R², including the N atom connected to R² andX, forming a heterocyclic group, and in X a C atom is optionallysubstituted by R¹⁰ and/or one or two C atoms are optionallyindependently substituted by one or two substituents selected fromC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl andC₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenylsubstituents are optionally joined together, forming a carbocyclic ringsystem, and wherein in the abovementioned groups and radicals one ormore C atoms are optionally mono- or polysubstituted by F and/or one ortwo C atoms are optionally independently monosubstituted by Cl or Br. 6.The compound according to claim 5, wherein X is —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, or —CH₂—CH═CH—CH₂— and, if Y is linked to X via a C atom,X is also —CH₂—CH═CH—, —CH₂—C═C—, —CH₂—CH₂-O—, —CH₂—CH₂—CH₂—O—,—CH₂—CH₂-NR⁴—, or —CH₂—CH₂—CH₂—NR⁴—, wherein the bridge X is optionallyconnected to R¹ including the N atom connected to R¹ and X, forming aheterocyclic group, and in X a C atom is optionally substituted by R¹⁰,and/or one or two C atoms are optionally independently substituted byone or two C₁₋₄-alkyl groups, wherein two alkyl groups are optionallyjoined together, forming a carbocyclic ring system, and one or more Catoms are optionally mono- or polysubstituted by F and/or one or two Catoms are optionally independently monosubstituted by Cl or Br.
 7. Thecompound according to claim 1, wherein Y is phenyl, pyridinyl, naphthyl,tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl,dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl and benzoxazolinyl,wherein Y is optionally independently mono- or polysubstituted at one ormore C atoms by R²⁰, and in the case of a phenyl group is optionallyadditionally monosubstituted by nitro, and/or at one or more N atoms areoptionally substituted by R²¹.
 8. The compound according to claim 7,wherein Y is

wherein each group is optionally mono- or polysubstituted at one or moreC atoms by R²⁰, and in the case of a phenyl group is optionallyadditionally monosubstituted by nitro, and/or one or more NH groups isoptionally substituted by R²¹.
 9. The compound according to claim 1,wherein A is phenyl, pyridyl, or naphthyl, wherein A is optionally mono-or polysubstituted at one or more C atoms by R²⁰, and in the case of aphenyl ring is optionally additionally monosubstituted by nitro.
 10. Thecompound according to claim 1, wherein b is
 0. 11. The compoundaccording to claim 1, wherein b is 1 and B is phenyl, furanyl, thienyl,or pyridyl, wherein B is optionally mono- or polysubstituted at one ormore C atoms by R²⁰, and in the case of a phenyl ring is optionallyadditionally monosubstituted by nitro.
 12. The compound according claim1, wherein Z is a single bond or —CH₂—CH₂—.
 13. The compound accordingto claim 1, wherein R³ is H or methyl.
 14. The compound according toclaim 1, wherein:

B is phenyl, wherein Y, A, and B are each optionally independently mono-or polysubstituted at one or more C atoms R²⁰, and in the case of aphenyl group, is optionally additionally monosubstituted by nitro; and bis 0 or
 1. 15. The compound according to claim 14, wherein: R¹ and R²are each independently H, C₁₋₆-alkyl, C₃₋₅-alkenyl, C₃₋₅-alkynyl,C₃₋₇-cycloalkyl, hydroxy-C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₃-alkyl,(hydroxy-C₃₋₇-cycloalkyl)-C₁₋₃-alkyl, hydroxy-C₂₄-alkyl, NC—C₂₋₃-alkyl,C₁₋₄-alkoxy-C₂₋₄-alkyl, hydroxy-C₁₋₄-alkoxy-C₂₋₄-alkyl,C₁₋₄-alkoxy-carbonyl-C₁₋₄-alkyl, carboxyl-C₁₋₄-alkyl, amino-C₂₋₄alkyl,C₁₋₄alkyl-amino-C₂₋₄-alkyl, di-(C₁₋₄-alkyl)-amino-C₂₋₄-alkyl,cyclo-C₃₋₆-alkyleneimino-C₂₋₄-alkyl, pyrrolidin-3-yl,N—(C₁₋₄-alkyl)-pyrrolidinyl, pyrrolidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-pyrrolidinyl-C₁₋₃-alkyl, piperidin-3-yl or -4-yl,N—(C₁₋₄-alkyl)-piperidin-3-yl or -4-yl, piperidinyl-C₁₋₃-alkyl,N—(C₁₋₄-alkyl)-piperidinyl-C₁₋₃-alkyl, tetrahydropyran-3-yl,tetrahydropyran-4-yl, tetrahydropyranyl-C₁₋₃-alkyl,tetrahydrofuran-3-yl, tetrahydrofuranyl-C₁₋₃-alkyl, phenyl,phenyl-C₁₋₃-alkyl, pyridyl, or pyridyl-C₁₋₃-alkyl, wherein in each groupone or more C atoms are optionally mono- or polysubstituted by F and/orone or two C atoms are optionally independently monosubstituted by Cl orBr, and each phenyl or pyridyl group is optionally mono- orpolysubstituted by R²⁰ and/or monosubstituted by nitro; and X is anunbranched C₁₋₄-alkylene bridge and, if Y is linked to X via a C atom,is also —CH₂—CH═CH—, —CH₂—C≡C—, C₂₋₄-alkylenoxy, or C₂₋₄-alkylene-NR⁴—,wherein the bridge X is optionally connected to R¹, including the N atomconnected to R¹ and X, forming a heterocyclic group, and the bridge X isoptionally additionally connected to R², including the N atom connectedto R² and X, forming a heterocyclic group, and in X a C atom isoptionally substituted by R¹⁰ and/or one or two C atoms are optionallyindependently substituted by one or two substituents selected fromC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, C₄₋₇-cycloalkenyl andC₄₋₇-cycloalkenyl-C₁₋₃-alkyl, while two alkyl and/or alkenylsubstituents are optionally joined together, forming a carbocyclic ringsystem, wherein in the abovementioned groups and radicals of X one ormore C atoms are optionally mono- or polysubstituted by F and/or one ortwo C atoms are optionally independently monosubstituted by Cl or Br.16. The compound according to claim 1, wherein: R²⁰ is halogen, hydroxy,cyano, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₃-alkyl, hydroxy-C₁₋₄-alkyl, and R²²—C₁₋₃-alkyl, orhas one of the meanings given for R²², and R²² is C₁₋₄-alkoxy,C₁₋₄-alkylthio, carboxy, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl,aminocarbonyl, C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,C₁₋₄-alkyl-sulfonyl, C₁₋₄-alkyl-sulfinyl, C₁₋₄-alkyl-sulfonylamino,amino, C₁₋₄-alkylamino-, di-(C₁₋₄-alkyl)-amino,C₁₋₄-alkyl-carbonylamino, hydroxy-C₁₋₃-alkylaminocarbonyl,aminocarbonylamino, or C₁₋₄-alkylaminocarbonylamino, wherein in each ofR²⁰ and R²² one or more C atoms are optionally mono- or polysubstitutedby F and/or one or two C atoms are optionally independently additionallymonosubstituted by Cl or Br.
 17. A physiologically acceptable salt ofthe compound according to one of claims 1 to
 16. 18. A pharmaceuticalcomposition comprising the compound according to one of claims 1 to 16and one or more physiologically acceptable excipients, inert carriers,or diluents.
 19. The pharmaceutical composition according to claim 18,further comprising a second active substance selected from the groupconsisting of active substances for the treatment of diabetes, activesubstances for the treatment of diabetic complications, activesubstances for the treatment of obesity, preferably other than MCHantagonists, active substances for the treatment of high blood pressure,active substances for the treatment of dyslipidemia or hyperlipidemia,including arteriosclerosis, active substances for the treatment ofarthritis, active substances for the treatment of anxiety states, andactive substances for the treatment of depression.
 20. A method ofinfluencing the eating behavior of a mammal comprising administering tothe mammal an effective amount of the compound according to claim
 1. 21.A method of reducing the body weight and/or for preventing an increasein the body weight of a mammal comprising administering to the mammal aneffective amount of the compound according to claim
 1. 22. A method ofpreventing and/or treating metabolic disorders and/or eating disordersin a patient, comprising administering to the patient an effectiveamount of the compound according to claim
 1. 23. The method of claim 22,wherein metabolic disorders and/or eating disorders are selected fromobesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa,and hyperphagia.
 24. A method of preventing and/or treating diabetes,diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulinresistance, pathological glucose tolerance, encephalorrhagia, cardiacinsufficiency, cardiovascular diseases, arthritis, or gonitisin in apatient, comprising administering to the patient an effective amount ofthe compound according to claim 1.